Organic compounds

ABSTRACT

The present invention provides novel organic compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     methods of use, and pharmaceutical compositions thereof.

The mineralocorticoid hormone aldosterone is produced by the adrenalgland and acts on the distal tubules and collecting ducts of the kidneyto increase reabsorption of ions and water in the kidney. Aldosteronecauses conservation of sodium, secretion of potassium, increased waterretention, and increased blood pressure.

Aldosterone has been implicated in the pathogenesis of cardiovasculardiseases such as hypertension and heart failure. In clinical trials,treatment with the nonselective mineralocorticoid receptor antagonist(MRA) spironolactone or the selective MRA eplerenone significantlyreduced morbidity and mortality among patients with heart failure ormyocardial infarction already taking an angiotensin-converting enzymeinhibitor or a β-blocker. However, significant side effects such asgynecomastia and impotence were observed in male patients receivingspironolactone while hyperkalemia was seen in patients taking eitherdrug.

The invention pertains to the compounds and methods for using them asdescribed herein. Examples of compounds of the invention include thecompounds of Formulae I-IV, and the compounds of the examples.

In another embodiment, the invention pertains, at least in part, to amethod for treating an aldosterone synthase-mediated disorder or diseasein a subject by administering to the subject a therapeutically effectiveamount of a compound of Formulae I-IV, such that the aldosteronesynthase-mediated disorder or disease in the subject is treated.

In yet another embodiment, the invention pertains, at least in part, toa method for treating a subject for hypokalemia, hypertension, Conn'sdisease, renal failure, in particular, chronic renal failure,restenosis, atherosclerosis, syndrome X, obesity, nephropathy,post-myocardial infarction, coronary heart diseases, increased formationof collagen, fibrosis and remodeling following hypertension andendothelial dysfunction, cardiovascular diseases, renal dysfunction,liver diseases, cerebrovascular diseases, vascular diseases,retinopathy, neuropathy, insulinopathy, edema, endothelial dysfunction,baroreceptor dysfunction, migraine headaches, heart failure such ascongestive heart failure, arrhythmia, diastolic dysfunction, leftventricular diastolic dysfunction, diastolic heart failure, impaireddiastolic filling, systolic dysfunction, ischemia, hypertropiccardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis,impaired arterial compliance, myocardial necrotic lesions, vasculardamage, myocardial infarction, left ventricular hypertrophy, decreasedejection fraction, cardiac lesions, vascular wall hypertrophy,endothelial thickening, or fibrinoid necrosis of coronary arteries,comprising administering to the subject a therapeutically effectiveamount of a compound of Formulae I-IV, such that the subject is treated.

In yet another embodiment, the invention pertains, at least in part, topharmaceutical compositions, comprising an effective amount of acompound of Formulae 1, II, III or IV, wherein said effective amount iseffective to treat an aldosterone synthase associated state.

An alternative approach to ameliorate the deleterious effects ofaldosterone is to suppress its production by inhibitors of aldosteronesynthase, an enzyme responsible for the final steps of the biosynthesisof aldosterone from deoxycorticosterone, via conversion ofcorticosterone to form 18-OH-corticosterone, which is then converted toaldosterone.

The invention pertains, at least in part, to compounds, pharmaceuticalcompositions containing the compound and methods of use thereof. Thepresent invention also relates to novel compounds which may be used, forexample, as modulators of aldosterone synthase, or inhibitors ofaldosterone synthesis.

The compounds of the present invention may, for example, be used totreat various aldosterone synthase associated states such ashypokalemia, hypertension, Conn's disease, renal failure, in particular,chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity,nephropathy, post-myocardial infarction, coronary heart diseases,increased formation of collagen, fibrosis and remodeling followinghypertension and endothelial dysfunction, cardiovascular diseases, renaldysfunction, liver diseases, cerebrovascular diseases, vasculardiseases, retinopathy, neuropathy, insulinopathy, edema, endothelialdysfunction, baroreceptor dysfunction, migraine headaches, heart failuresuch as congestive heart failure, arrhythmia, diastolic dysfunction,left ventricular diastolic dysfunction, diastolic heart failure,impaired diastolic filling, systolic dysfunction, ischemia, hypertropiccardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis,impaired arterial compliance, myocardial necrotic lesions, vasculardamage, myocardial infarction, left ventricular hypertrophy, decreasedejection fraction, cardiac lesions, vascular wall hypertrophy,endothelial thickening, and fibrinoid necrosis of coronary arteries.

COMPOUNDS OF THE INVENTION

The present invention pertains, at least in part, to compounds ofFormula I:

wherein:

R^(1a), R^(2a), R^(3a), and R^(4a) are each independently hydrogen,halogen, cyano, hydroxy, alkoxy, alkyl, alkenyl, or alkoxycarbonyl;

R^(5a) is hydrogen halogen, cyano, alkyl, alkenyl, arylalkyl,heteroarylalkyl, aminocarbonyl, alkylaminocarbonyl, carboxylate,alkoxycarbonyl, heterocyclylcarbonyl, aryl, or heteroaryl;

R^(6a) and R^(7a) are each independently hydrogen, halogen, hydroxy,alkoxy, amino, alkyl, sulfonyl, —O-sulfonyl, alkylamino, heterocyclyl,aminocarbonyl, carboxylate, or alkoxycarbonyl;

R^(8a) is hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkoxycarbonyl,sulfonyl, aroyl, aryl, or heteroaryl; and pharmaceutically acceptablesalts, polymorphs, rotamers, prodrugs, enantiomers, hydrates, andsolvates thereof;

with the proviso that at least one of R^(1a)-R^(8a) is other thanhydrogen; and when R^(3a) is lower alkyl or halogen, then at least oneof R^(1a), R^(2a) and R^(4a)-R^(8a) is other than hydrogen; and whenR^(5a) is cyano or lower alkyl optionally substituted with cyano,—C(O)-piperidine, amino, alkylamino, dialkylamino, carboxylate,alkoxycarbonyl, aminocarbonyl, or heterocyclyl, then at least one ofR^(1a)-R^(4a) and R^(6a)-R^(8a) is other than hydrogen; and when R^(7a)is imidazolyl, then at least one of R^(1a)-R^(6a) and R^(8a) is otherthan hydrogen; and when R^(8a) is lower alkyl, arylalkyl oralkoxycarbonyl, then at least one of R^(1a)-R^(7a) is other thanhydrogen; and when R^(5a) is lower alkyl and R^(8a) is alkyl substitutedwith carboxylate or PO₃R²¹R²² wherein R²¹ and R²² are each independentlyhydrogen or lower alkyl, then at least one of R^(1a)-R^(4a) and R^(6a)and R^(7a) is other than hydrogen; and when R^(3a) is halogen and R^(5a)and R^(8a) are independently lower alkyl optionally substituted withcarboxylate, alkoxycarbonyl, or —C(O)-piperidine, then at least one ofR^(1a), R^(2a), R^(4a), R^(6a) and R^(7a) is other than hydrogen; andwhen R^(5a) is lower alkenyl substituted with heteroaryl and R^(8a) islower alkyl, then at least one of R^(1a)-R^(4a), R^(6a) and R^(7a) isother than hydrogen; and when R^(3a) is halogen or lower alkyl andR^(5a) is lower alkyl substituted with dialkylamino,dialkylaminocarbonyl, carboxylate, alkoxycarbonyl or aminocarbonyl, thenat least one of R^(1a), R^(2a), R^(4a), and R^(6a)-R^(8a) is other thanhydrogen; and when R^(3a) is —O-benzyl and R^(5a) is alkyl-NH₂, then atleast one of R^(1a), R^(2a), R^(4a), and R^(6a)-R^(8a) is other thanhydrogen; and when R^(2a) and R^(3a) are each alkoxy and R^(5a) iscyano, then at least one of R^(1a), R^(4a), and R⁶-R^(8a) is other thanhydrogen; and when R^(1a) and R^(3a) are each halogen and R^(5a) isalkyl-NH₂, then at least one of R^(2a), R^(4a), and R^(6a)-R^(2a) isother than hydrogen; and when R^(2a) is alkoxycarbonyl and R^(4a) ishalogen, then at least one of R^(1a), R^(3a), R^(5a) and R^(6a)-R^(8a)is other than hydrogen; and when R^(5a) is alkyl and R^(7a) is—OCH₂—(N-methylpyrrolidine), then at least one of R^(1a)-R^(4a), R^(6a)and R^(8a) is other than hydrogen; and when R^(3a) is cycloalkyl andR^(5a) is alkyl-NH₂, then at least one of R^(1a), R^(2a), R^(4a), andR^(6a)-R^(8a) is other than hydrogen; and when R^(3a) is alkylsubstituted with aroyl, and R⁵ and R⁸ are each independently hydrogen orlower alkyl, then at least one of R^(1a), R^(2a), and R^(4a) is otherthan hydrogen.

Examples of R^(1a) include hydrogen, halogen (e.g., chlorine orfluorine), hydroxy, and alkoxy (e.g., methoxy).

In a further embodiment, R^(1a) is optionally substituted alkyl (e.g.,methyl, ethyl, or propyl), which may be substituted with groups such ascarboxylate, hydroxy, alkylamino (e.g., ethylamino) which may be furthersubstituted with hydroxy, and aryl (e.g., phenyl) which may be furthersubstituted with carboxylate.

In yet a further embodiment, R^(1a) is optionally substituted alkenyl(e.g., alkenyl is ethenyl or propenyl), which may be substituted withgroups such as hydroxy, alkoxycarbonyl (e.g., butoxycarbonyl), and aryl(e.g., phenyl) which may be further substituted with alkoxycarbonyl(e.g., methoxycarbonyl).

In one embodiment, R^(2a) includes hydrogen, halogen (e.g., chlorine orfluorine), hydroxy, alkyl (e.g., methyl), and alkoxy (e.g., methoxy).

Examples of R^(3a) include, hydrogen, halogen (e.g., chlorine orfluorine), alkoxy (e.g., methoxy), cyano, and alkoxycarbonyl (e.g.,methoxycarbonyl).

In a further embodiment, R^(3a) is optionally substituted alkyl (e.g.,methyl or ethyl), which may be substituted with groups such ascarboxylate, alkoxycarbonyl (e.g., ethoxycarbonyl), hydroxy, andhalogen. This optionally substituted alkyl may be, for exampletrifluoromethyl.

Examples of R^(4a) include, hydrogen, halogen (e.g., fluorine), andcyano.

In one embodiment, R^(5a) includes hydrogen, halogen (e.g., bromine),alkenyl (e.g., propenyl), cyano, —C(O)NH₂, carboxylate, alkoxycarbonyl(e.g., methoxycarbonyl or isopropoxycarbonyl), arylalkyl (e.g., benzyl),heteroarylalkyl (e.g., imidazolylmethyl), heterocyclylcarbonyl (e.g.,pyrrolidinylcarbonyl), alkylaminocarbonyl (e.g., ethylaminocarbonyl),and aryl (e.g., phenyl).

In another embodiment, R^(5a) includes optionally substituted alkyl(e.g., methyl, ethyl, propyl or butyl), which may be substituted withgroups such as hydroxy, alkoxy (e.g., ethoxy), and carboxylate.

In yet another embodiment, R^(5a) includes optionally substitutedheteroaryl (e.g., 1,2,4-oxadiazolyl), which may be substituted withgroups such as alkyl (e.g., methyl).

Examples of R^(6a) and R^(7a) include alkoxy (e.g., methoxy, ethoxy, orbenzyloxy), which may be substituted with hydroxy or aryl (e.g.,phenyl); halogen (e.g., chlorine or fluorine); hydroxy; sulfonyl, whichmay be substituted with aryl (e.g., phenylsulfonyl) or alkyl (e.g.,butylsulfonyl); alkylamino (e.g., ethylamino); carboxylate;alkoxycarbonyl (e.g., ethoxycarbonyl); aminocarbonyl; and amino (e.g.,—NH(S(O)₂(CH₃)₂, —NR′—S(O)₂-alkyl, —NR′—C(O)-alkyl, —NR′−C(O)—NR′-alkyl,and —NR′—C(O)—O-alkyl, wherein each R′ is independently hydrogen,C₁-C₄-alkyl, or C₃-C₆-cycloalkyl). In another embodiment, R^(6a) is—NH—S(O)₂—CH₃.

In one embodiment, R^(6a) and R^(7a) includes optionally substitutedheterocyclyl (e.g., piperazinyl), which may be substituted with groupssuch as alkyl (e.g., methyl).

In another embodiment, R^(6a) and R^(7a) includes optionally substitutedalkyl (e.g., methyl or ethyl), which may be substituted with groups suchas heterocyclyl (e.g., morpholinyl, piperazinyl, pyrrolidinyl, orthiomorpholinyl dioxide), which may itself be substituted with alkyl(e.g., methyl) or —NH₂; hydroxy; alkoxy (e.g., methoxy); or halogen.This optionally substituted alkyl may be, for example, trifluoromethyl.

In another embodiment, R^(6a) and R^(7a) includes optionally substitutedalkyl (e.g., methyl or ethyl), which may be substituted with amino(e.g., —NR^(30b)R^(31b)). Examples of R^(30b) include hydrogen andmethyl. Examples of R^(31b) include alkoxycarbonyl (e.g.,ethoxycarbonyl); alkylaminocarbonyl (e.g., ethylaminocarbonyl);heterocyclylcarbonyl (e.g., morpholinyl); acyl (e.g., —C(O)(CH₂)₂CH₃);alkyl (e.g., ethyl), which may optionally be substituted with hydroxy;sulfonyl, which may be substituted with benzyl; dialkylamino (e.g.,diethylaminosulfonyl); alkyl (e.g., methylsulfonyl, ethylsulfonly,propylsulfonyl, butylsulfonyl, or trifluoromethylsulfonyl); or aryl(e.g., phenylsulfonyl). This phenylsulfonyl may be, for example, furthersubstituted with halogen (e.g., fluorine).

In another embodiment, R^(6a) and R^(7a) includes optionally substituted—O-sulfonyl, which may be substituted with groups such as alkyl (e.g.,methyl); amino (e.g., dimethylamino, diethylamino, or —N(Et)(benzyl));or heterocyclyl (e.g., morpholinyl, piperazinyl, N-methyl piperazinyl,or pyrrolidinyl).

In one embodiment, R^(8a) includes hydrogen, heteroaryl (e.g.,3-pyridinyl), and alkoxycarbonyl (e.g., isopropoxycarbonyl orbutoxycarbonyl).

In another embodiment, R^(8a) includes optionally substituted arylalkyl(e.g., benzyl), which may be substituted with groups at the paraposition and/or at the meta position. Examples of such groups includealkoxycarbonyl (e.g., methoxycarbonyl); carboxylate; alkyl (e.g.,methyl); cyano; alkoxy (e.g., methoxy); halogen (e.g., fluorine);sulfonyl, which is optionally substituted with alkyl (e.g.,methylsulfonyl); heteroaryl (e.g., tetrazolyl); alkoxy (e.g., methoxy orbenzyloxy); or combinations thereof.

In yet another embodiment, R^(8a) includes optionally substitutedheteroarylalkyl (e.g., benzoimidizolyl methyl, 1,2,3-triazolylmethyl, orisoxazolyl methyl), which may be substituted with alkyl (e.g., methyl),which may optionally be further substituted with aryl (e.g., phenyl)such that R^(8a) is heteroarylalkyl substituted with benzyl.

In another embodiment, R^(8a) includes optionally substituted aroyl(e.g., benzoyl), which may be substituted with groups at the paraposition and/or at the meta position. Examples of such groups includecyano, alkyl (e.g., methyl or ethyl), alkoxy (e.g., methoxy ordimethoxy), alkoxycarbonyl (e.g., butoxycarbonyl), carboxylate, orcombinations thereof.

In another embodiment, R^(8a) includes optionally substituted alkyl(e.g., methyl, ethyl, propyl, isopropyl or butyl), which may besubstituted with groups such as —NHC(O)R^(20a) and —OC(O)R^(20a),wherein R^(20a) is alkyl (e.g., butyl).

In yet another embodiment, R^(8a) includes optionally substituted alkyl(e.g., methyl, ethyl, propyl, isopropyl or butyl), which may besubstituted with groups such as cycloalkyl (e.g., cyclohexyl);carboxylate; hydroxy; alkoxycarbonyl (e.g., butoxycarbonyl); andsulfonyl, which is optionally substituted with aryl (e.g.,phenylsulfonyl).

In still another embodiment, R^(8a) includes optionally substitutedalkyl (e.g., methyl, ethyl, propyl, isopropyl or butyl), which may besubstituted with groups such as heterocyclyl (e.g., piperazinyl orazetidyl), which may itself be substituted with groups such as alkyl,dialkyl (e.g., dimethyl), and ═O.

In yet another embodiment, R^(8a) includes optionally substituted alkyl(e.g., methyl, ethyl, propyl, isopropyl or butyl), which may besubstituted with groups such as heterocyclylcarbonyl (e.g.,piperazinylcarbonyl), which may itself be substituted with groups suchas alkyl or dialkyl (e.g., dimethyl); aryl (e.g., phenyl), which mayitself be substituted with groups such as carboxylate; and alkoxy (e.g.,methoxy, ethoxy, propoxy, butoxy, pentoxy, or phenoxy), which may itselfbe substituted with groups such as alkoxycarbonyl (e.g., methoxycarbonylor ethoxycarbonyl), carboxylate, and hydroxy.

In one embodiment, R^(8a) is phenoxy substituted alkyl (e.g., methyl,ethyl, propyl, isopropyl or butyl), and this phenoxy is optionallysubstituted at the para position and/or at the meta position with groupssuch as alkoxycarbonyl (e.g., methoxycarbonyl or ethoxycarbonyl),carboxylate, and hydroxy.

Another example of R^(8a) includes optionally substituted aryl (e.g.,phenyl), which may be substituted at the para position and/or at themeta position with groups such as cyano, alkoxy (e.g., methoxy), orcombinations thereof.

Another example of R^(8a) includes optionally substituted sulfonyl,which may be substituted with groups such as aryl (e.g., phenyl), whichmay itself be substituted with groups such as alkyl (e.g., methyl),carboxylate, or combinations thereof.

In one embodiment of the present invention R^(8a) is hydrogen, methyl,ethyl, cyano, carboxylate, or alkoxycarbonyl.

In another embodiment of the present invention R^(8a) is hydrogen,methyl, ethyl, benzyl-CO₂H, or benzyl-CO₂Me.

In yet another embodiment, R^(8a) is:

L is alkyl, carbonyl, sulfonyl, or —(CH₂)₂—O—; and

R^(11a), R^(12a), R^(13a), R^(14a), and R^(15a) are each independentlyhydrogen, alkyl, cyano, halogen, alkoxy, alkoxycarbonyl, carboxylate,heteroaryl, or sulfonyl.

Each of the aforementioned groups R^(1a), R^(2a), R^(3a), R^(4a),R^(5a), R^(6a) and R^(8a) may be optionally substituted.

Another embodiment of Formula (I), wherein:

R^(1a) is hydrogen, halogen, hydroxy, alkoxy, alkyl, or alkenyl;

R^(2a) is hydrogen, halogen, alkyl, hydroxy, or alkoxy;

R^(3a) is hydrogen, halogen, cyano, alkoxy, alkyl, or alkoxycarbonyl;

R^(4a) is hydrogen, halogen, or cyano;

R^(5a) is hydrogen, halogen, cyano, alkyl, alkenyl, arylalkyl,heteroarylalkyl, aminocarbonyl, alkylaminocarbonyl, carboxylate,alkoxycarbonyl, heterocyclylcarbonyl, aryl, or heteroaryl;

R^(6a) and R^(7a) are each independently hydrogen, halogen, hydroxy,alkoxy, amino, alkyl, sulfonyl, —O-sulfonyl, alkylamino, heterocyclyl,aminocarbonyl, carboxylate, or alkoxycarbonyl; and

R^(8a) is hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkoxycarbonyl,sulfonyl, aroyl, aryl, or heteroaryl.

Another embodiment of Formula (I), wherein:

R^(5a) is hydrogen, cyano, methyl, ethyl, carboxylate, ormethoxycarbonyl.

Another embodiment of Formula (I), wherein:

R^(8a) is hydrogen, methyl, ethyl, benzyl-CO₂H, or benzyl-CO₂Me.

Another embodiment of Formula (I), wherein:

R^(1a) is hydrogen;

R^(2a) is hydrogen, halogen, or hydroxy;

R^(3a) is hydrogen, halogen, cyano, or alkoxy;

R^(4a) is hydrogen or halogen;

R^(5a) is hydrogen or alkyl;

R^(6a) and R^(7a) are hydrogen;

R^(8a) is:

L is alkyl, carbonyl, sulfonyl, or —(CH₂)₂—O—; and

R^(11a), R^(12a), R^(13a), R^(14a), and R^(15a) are each independentlyhydrogen, alkyl, cyano, halogen, alkoxy, alkoxycarbonyl, carboxylate,heteroaryl, or sulfonyl.

Another embodiment of Formula (I), wherein:

R^(11a) and R^(15a) are each independently hydrogen, alkyl, cyano,halogen, or alkoxy;

R^(12a) and R^(14a) are each independently hydrogen, alkyl, cyano,halogen, alkoxy, alkoxycarbonyl, carboxylate, heteroaryl, or sulfonyl;and

R^(13a) is hydrogen, alkyl, cyano, alkoxy, alkoxycarbonyl, carboxylate,heteroaryl, or sulfonyl.

In yet another embodiment, the invention pertains, at least in part, tocompounds of Formula II:

wherein:

R^(2q) is hydrogen or halogen;

R^(3q) is hydrogen, halogen, or cyano;

R^(5q) is hydrogen, alkyl, or cyano;

R^(7q) is hydrogen, halogen, alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl,—NR′—SO₂-alkyl, —NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl, —NR′—C(O)—O-alkyl,haloalkyl, or alkyl optionally substituted with heterocyclyl,—NR′—SO₂-alkyl, —NR′—SO₂-haloalkyl, NR′—C(O)-alkyl,NR′—C(O)-heterocyclyl, —NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl;

R^(8q) is hydrogen, alkyl, hydroxyalkyl, -alkyl-OC(O)-alkyl,carboxylate, alkoxycarbonyl, or arylalkyl substituted with alkyl, oraroyl substituted with cyano and/or alkyl, or -alkyl-O-aryl substitutedwith alkoxycarbonyl;

each R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl; andpharmaceutically acceptable salts, polymorphs, rotamers, prodrugs,enantiomers, hydrates, and solvates thereof,

with the proviso that at least one of R^(2q), R^(3q), R^(5q), R^(7q) andR^(8q) is other than hydrogen; and when R^(8q) is lower alkyl oralkoxycarbonyl, then at least one of R^(2q), R^(3q), R^(5q) and R^(7q)is other than hydrogen; and when R^(5q) is cyano, then at least one ofR^(2q), R^(3q), and R^(8q) is other than hydrogen.

In another embodiment, R^(7q) is alkoxy or alkyl substituted withheterocyclyl and R^(8q) is alkyl.

Another embodiment of Formula (II), wherein R^(7q) is alkoxy or alkylsubstituted with heterocyclyl and R^(8q) is alkyl.

Another embodiment of Formula (II), wherein

R^(2q) is hydrogen or halogen;

R^(3q) is hydrogen, or halogen;

R^(5q) is hydrogen or cyano;

R^(7q) alkyl optionally substituted with heterocyclyl, —NR′—SO₂-alkyl,—NR′—SO₂-haloalkyl, NR′—C(O)-alkyl, NR′—C(O)-heterocyclyl,—NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl;

R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl; and

R^(8q) is hydrogen, or C₁₋₆alkyl.

Another embodiment of Formula (II), wherein

R^(2q) is hydrogen or halogen;

R^(3q) is hydrogen, or halogen;

R^(5q) is hydrogen or cyano;

R^(7q) is C₁₋₄alkyl optionally substituted with heterocyclyl,—NR′—SO₂—C₁₋₄alkyl, —NR′—SO₂-haloC₁₋₄alkyl, NR′—C(O)—C₁₋₄alkyl,NR′—C(O)-heterocyclyl, —NR′—C(O)—NR′—C₁₋₄alkyl, or—NR′—C(O)—O—C₁₋₄alkyl;

R′ is independently hydrogen, or C₁-C₄-alkyl; and

R^(8q) is hydrogen, or C₁₋₆alkyl.

Another embodiment of Formula (II), wherein

R^(7q) is C₁₋₄alkyl substituted with —NR′—SO₂—C₁₋₄alkyl,—NR′—SO₂-haloC₁₋₄alkyl, or NR′—C(O)—C₁₋₄alkyl;

R′ is independently hydrogen, or C₁-C₄-alkyl; and

R^(8q) is hydrogen, methyl, or ethyl.

In yet another embodiment, the invention pertains, at least in part, tocompounds of Formula III:

wherein:

R^(2b) is hydrogen or halogen;

R^(3b) is hydrogen, halogen, or cyano;

R^(5b) is alkyl;

R^(7b) is hydrogen, halogen, alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl,—NR′—SO₂-alkyl, —NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl, —NR′—C(O)—O-alkyl,haloalkyl, or alkyl optionally substituted with heterocyclyl,—NR′—SO₂-alkyl, —NR′—SO₂-haloalkyl, NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl,NR′—C(O)-heterocyclyl, or —NR′—C(O)—O-alkyl;

R^(8b) is hydrogen, alkyl, hydroxyalkyl, -alkyl-OC(O)-alkyl,carboxylate, alkoxycarbonyl, or arylalkyl substituted with alkyl, oraroyl substituted with cyano and/or alkyl, or -alkyl-O-aryl substitutedwith alkoxycarbonyl;

each R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl; andpharmaceutically acceptable salts, polymorphs, rotamers, prodrugs,enantiomers, hydrates, and solvates thereof.

Another embodiment of Formula (III), wherein

R^(2b) is hydrogen or halogen;

R^(3b) is hydrogen, halogen, or cyano;

R^(5b) is C₁₋₄alkyl;

R^(7b) is hydrogen, halogen, C₁₋₄alkoxy, —OSO₂-heterocyclyl,—O-arylalkyl, —NR′—SO₂—C₁₋₄alkyl, —NR′—C(O)—C₁₋₄alkyl,—NR′—C(O)—NR′—C₁₋₄alkyl, —NR′—C(O)—O-alkyl, haloalkyl, or C₁₋₄alkyloptionally substituted with heterocyclyl, —NR′—SO₂—C₁₋₄alkyl,—NR′—SO₂-halo C₁₋₄alkyl, NR′—C(O)—C₁₋₄alkyl, —NR′—C(O)—NR′—C₁₋₄alkyl,NR′—C(O)-heterocyclyl, or —NR′—C(O)—O—C₁₋₄alkyl;

R^(8b) is hydrogen, C₁₋₄alkyl, hydroxyalkyl, —C₁₋₄alkyl-OC(O)—C₁₋₄alkyl,carboxylate, alkoxycarbonyl, or arylalkyl substituted with C₁₋₄alkyl, oraroyl substituted with cyano and/or C₁₋₄alkyl, or —C₁₋₄alkyl-O-arylsubstituted with alkoxycarbonyl;

each R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl; andpharmaceutically acceptable salts, polymorphs, rotamers, prodrugs,enantiomers, hydrates, and solvates thereof.

Another embodiment of Formula (III), wherein

R^(2b) is hydrogen or halogen;

R^(3b) is hydrogen, halogen, or cyano;

R^(5b) is methyl, ethyl or isopropyl;

R^(7b) is C₁₋₄alkyl substituted with —NR′—SO₂—C₁₋₄alkyl,—NR′—SO₂-haloC₁₋₄alkyl, NR′—C(O)—C₁₋₄alkyl, or —NR′—C(O)—NR′—C₁₋₄alkyl;

R^(8b) is hydrogen, methyl or ethyl;

each R′ is independently hydrogen, or C₁-C₄-alkyl.

In yet another embodiment, the invention pertains, at least in part, tocompounds of Formula IV:

wherein:

R^(2c) is hydrogen or halogen;

R^(3c) is hydrogen, halogen, or cyano;

R^(5c) is cyano; and

R^(7c) is hydrogen, halogen alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl,—NR′—SO₂-alkyl, —NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl, —NR′—C(O)—O-alkylor alkyl optionally substituted with heterocyclyl, —NR′—SO₂-alkyl,—NR′—SO₂-haloalkyl, NR′—C(O)-alkyl, NR′—C(O)-heterocyclyl,—NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl;

R^(8c) is alkyl;

each R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl; andpharmaceutically acceptable salts, polymorphs, rotamers, prodrugs,enantiomers, hydrates, and solvates thereof.

Another embodiment of Formula (IV), wherein

R^(2c) is hydrogen or halogen;

R^(3c) is hydrogen, halogen, or cyano;

R^(5c) is cyano; and

R^(7c) is hydrogen, halogen, C₁₋₄alkoxy, —OSO₂-heterocyclyl,—O-arylalkyl, —NR′—SO₂—C₁₋₄ alkyl, —NR′—C(O)—C₁₋₄ alkyl,—NR′—C(O)—NR′—C₁₋₄ alkyl, —NR′—C(O)—O—C₁₋₄ alkyl or C₁₋₄ alkyloptionally substituted with heterocyclyl, —NR′—SO₂—C₁₋₄ alkyl,—NR′—SO₂-halo C₁₋₄ alkyl, NR′—C(O)—C₁₋₄ alkyl, NR′—C(O)-heterocyclyl,—NR′—C(O)—NR′—C₁₋₄ alkyl, or —NR′—C(O)—O—C₁₋₄ alkyl;

R^(8c) is C₁₋₄ alkyl;

each R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl; andpharmaceutically acceptable salts, polymorphs, rotamers, prodrugs,enantiomers, hydrates, and solvates thereof.

Another embodiment of Formula (III), wherein

R^(2c) is hydrogen or halogen;

R^(3c) is hydrogen, or halogen;

R^(5c) is cyano; and

R^(7c) is C₁₋₄ alkyl optionally substituted with —NR′—SO₂—C₁₋₄ alkyl,—NR′—SO₂-halo C₁₋₄ alkyl, NR′—C(O)—C₁₋₄ alkyl;

R^(8c) is C₁₋₄ alkyl;

each R′ is independently hydrogen or C₁-C₄-alkyl.

Another embodiment of Formula (IV), wherein

R^(7c) is C₁₋₄ alkyl substituted with —NR′—SO₂—C₁₋₄ alkyl, —NR′—SO₂-haloC₁₋₄ alkyl, NR′—C(O)—C₁₋₄ alkyl; and

each R′ is independently hydrogen, methyl, ethyl or propyl.

DEFINITIONS

The term “alkyl” includes saturated aliphatic groups, includingstraight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups(isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups(cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl),alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkylgroups. The term alkyl further includes alkyl groups, which can furtherinclude oxygen, nitrogen, sulfur or phosphorous atoms replacing one ormore carbons of the hydrocarbon backbone. In certain embodiments, astraight chain or branched chain alkyl has 6 or fewer carbon atoms inits backbone (e.g., C₁-C₆ for straight chain, C₃-C₆ for branched chain),and more preferably 4 or fewer. Likewise, preferred cycloalkyls havefrom 3-8 carbon atoms in their ring structure, and more preferably have5 or 6 carbons in the ring structure. The term C₁-C₆ includes alkylgroups containing 1 to 6 carbon atoms.

Moreover, the term alkyl includes both “unsubstituted alkyls” and“substituted alkyls,” the latter of which refers to alkyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example,alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety. Cycloalkyls can be further substituted, e.g.,with the substituents described above. An “alkylaryl” or an “arylalkyl”moiety is an alkyl substituted with an aryl (e.g.,phenylmethyl(benzyl)). The term “alkyl” also includes the side chains ofnatural and unnatural amino acids.

The term “aryl” includes groups, including 5- and 6-membered single-ringaromatic groups that may include from zero to four heteroatoms, forexample, benzene, phenyl, pyrrole, furan, thiophene, thiazole,isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole,isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, etc.Furthermore, the term “aryl” includes multicyclic aryl groups, e.g.,tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole,benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl,quinoline, isoquinoline, napthridine, indole, benzofuran, purine,benzofuran, deazapurine, or indolizine. Those aryl groups havingheteroatoms in the ring structure may also be referred to as “arylheterocycles,” “heterocycles,” “heteroaryls” or “heteroaromatics.”

Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-,or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl,tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl. A heteroaryl groupmay be mono-, bi-, tri-, or polycyclic.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more aryl, cycloaliphatic, or heterocyclylrings, where the radical or point of attachment is on the heteroaromaticring. Non-limiting examples include but are not limited to 1-, 2-, 3-,5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-,3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-,4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-,6-, 7-, or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-,3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl,3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-,2-, 3-, 4-, 5-, 6-, 7-, or 8-4-aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-,7-, or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-,2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-,6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-,3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl,2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-,6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-,or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl,2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl,1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-,8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-,or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxazinyl, 2-,4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-,or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroaryl groupsinclude, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl.

The aromatic ring of an “aryl” or “heteroaryl” group can be substitutedat one or more ring positions with such substituents as described above,as for example, halogen, hydroxy, alkoxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl,alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl,alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can alsobe fused or bridged with alicyclic or heterocyclic rings which are notaromatic so as to form a polycycle (e.g., tetralin).

The term “alkenyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, but thatcontain at least one double bond.

For example, the term “alkenyl” includes straight-chain alkenyl groups(e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl,octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups,cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, and cyclooctenyl), alkyl or alkenylsubstituted cycloalkenyl groups, and cycloalkyl or cycloalkenylsubstituted alkenyl groups. The term alkenyl further includes alkenylgroups which include oxygen, nitrogen, sulfur or phosphorous atomsreplacing one or more carbons of the hydrocarbon backbone. In certainembodiments, a straight chain or branched chain alkenyl group has 6 orfewer carbon atoms in its backbone (e.g., C₂-C₆ or straight chain, C₃-C₆for branched chain). Likewise, cycloalkenyl groups may have from 3-8carbon atoms in their ring structure, and more preferably have 5 or 6carbons in the ring structure. The term C₂-C₆ includes alkenyl groupscontaining 2 to 6 carbon atoms.

Moreover, the term alkenyl includes both “unsubstituted alkenyls” and“substituted alkenyls,” the latter of which refers to alkenyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “alkynyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one triple bond.

For example, the term “alkynyl” includes straight-chain alkynyl groups(e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkylor cycloalkenyl substituted alkynyl groups. The term alkynyl furtherincludes alkynyl groups which include oxygen, nitrogen, sulfur orphosphorous atoms replacing one or more carbons of the hydrocarbonbackbone. In certain embodiments, a straight chain or branched chainalkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆ for branched chain). The term C₂-C₆ includesalkynyl groups containing 2 to 6 carbon atoms.

Moreover, the term alkynyl includes both “unsubstituted alkynyls” and“substituted alkynyls,” the latter of which refers to alkynyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

Unless the number of carbons is otherwise specified, the term “loweralkyl” means an alkyl group, as defined above, but having from one tofive carbon atoms in its backbone structure. “Lower alkenyl” and “loweralkynyl” have chain lengths of, for example, 2-5 carbon atoms.

The term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl,and alkynyl groups covalently linked to an oxygen atom. Examples ofalkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy,and pentoxy groups. Examples of substituted alkoxy groups includehalogenated alkoxy groups. The alkoxy groups can be substituted withgroups such as alkenyl, alkynyl, halogen, hydroxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moieties. Examples ofhalogen substituted alkoxy groups include, but are not limited to,fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy,dichloromethoxy, trichloromethoxy, etc.

The term “acyl” includes compounds and moieties which contain the acylradical (CH₃CO—) or a carbonyl group. It includes substituted acylmoieties. The term “substituted acyl” includes acyl groups where one ormore of the hydrogen atoms are replaced by for example, alkyl groups,alkynyl groups, halogens, hydroxy, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moiety.

The term “acylamino” includes moieties wherein an acyl moiety is bondedto an amino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

The term “aroyl” includes compounds and moieties with an aryl orheteroaromatic moiety bound to a carbonyl group. Examples of aroylgroups include phenylcarboxy, naphthyl carboxy, etc. It includessubstituted aroyl moieties. The term “substituted aroyl” includes aroylgroups where one or more of the hydrogen atoms are replaced by forexample, alkyl groups, alkynyl groups, halogens, hydroxy,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, cyano,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The terms “alkoxyalkyl,” “alkylaminoalkyl” and “thioalkoxyalkyl” includealkyl groups, as described above, which further include oxygen, nitrogenor sulfur atoms replacing one or more carbons of the hydrocarbonbackbone, e.g., oxygen, nitrogen or sulfur atoms.

The term “carbamoyl” includes H₂NC(O)—, alkyl-NHC(O)—, (alkyl)₂NC(O)—,aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aryl-alkyl-NHC(O)—, alkyl(aryl-alkyl)-NC(O)—,etc. The term includes substituted carbamoyl moieties.

The term “sulfonyl” includes R—SO₂—, wherein R is hydrogen, alkyl, aryl,heteroaryl, aryl-alkyl, heteroaryl-alkyl, alkoxy, aryloxy, cycloalkyl,or heterocyclyl.

The term “sulfonamido” includes alkyl-S(O)₂—NH—, aryl-S(O)₂—NH—,aryl-alkyl-S(O)₂—NH—, heteroaryl-S(O)₂—NH—, heteroaryl-alkyl-S(O)₂—NH—,alkyl-S(O)₂—N(alkyl)-, aryl-S(O)₂—N(alkyl)-, aryl-alkyl-S(O)₂—N(alkyl)-,heteroaryl-S(O)₂—N(alkyl)-, heteroaryl-alkyl-S(O)₂—N(alkyl)-, etc. Theterm includes substituted carbamoyl moieties

The term “heterocyclyl” or “heterocyclo” includes an optionallysubstituted, saturated or unsaturated non-aromatic ring or ring system,e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-,11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-memberedtricyclic ring system and contains at least one heteroatom selected fromO, S and N, where the N and S can also optionally be oxidized to variousoxidation states. The heterocyclic group can be attached at a heteroatomor a carbon atom. The heterocyclyl can include fused or bridged rings aswell as spirocyclic rings. Examples of heterocycles includetetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine,1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine,imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran,oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane,thiomorpholine, etc.

The term “heterocyclyl” includes heterocyclic groups as defined hereinsubstituted with 1, 2 or 3 substituents such as alkyl, hydroxy (orprotected hydroxy), halo, oxo (e.g., ═O), amino, alkylamino ordialkylamino, alkoxy, cycloalkyl, carboxyl, heterocyclooxy, whereinheterocyclooxy denotes a heterocyclic group bonded through an oxygenbridge, alkyl-O—C(O)—, mercapto, nitro, cyano, sulfamoyl or sulfonamide,aryl, alkyl-C(O)—O—, aryl-C(O)—O—, aryl-S—, aryloxy, alkyl-S—, formyl(e.g., HC(O)—), carbamoyl, aryl-alkyl-, and aryl substituted with alkyl,cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(O)—NH—, alkylamino,dialkylamino or halogen.

The term “sulfamoyl” includes H₂NS(O)₂—, alkyl-NHS(O)₂—,(alkyl)₂NS(O)₂—, aryl-NHS(O)₂—, alkyl(aryl)-NS(O)₂—, (aryl)₂NS(O)₂—,heteroaryl-NHS(O)₂—, (aryl-alkyl)-NHS(O)₂—, (heteroaryl-alkyl)-NHS(O)₂—,etc. The term includes substituted sulfamoyl moieties.

The term “aryloxy” includes both an —O-aryl and an —O-heteroaryl group,wherein aryl and heteroaryl are defined herein. The term includessubstituted aryloxy moieties.

The term “amine” or “amino” includes compounds where a nitrogen atom iscovalently bonded to at least one carbon or heteroatom. The termincludes “alkyl amino” which comprises groups and compounds wherein thenitrogen is bound to at least one additional alkyl group. The term“dialkyl amino” includes groups wherein the nitrogen atom is bound to atleast two additional alkyl groups. The term “arylamino” and“diarylamino” include groups wherein the nitrogen is bound to at leastone or two aryl groups, respectively. The term “alkylarylamino,”“alkylaminoaryl” or “arylaminoalkyl” refers to an amino group which isbound to at least one alkyl group and at least one aryl group. The term“alkaminoalkyl” refers to an alkyl, alkenyl, or alkynyl group bound to anitrogen atom which is also bound to an alkyl group. The term “amine” or“amino” also includes substituted moieties.

The term “amide,” “amido” or “aminocarbonyl” includes compounds ormoieties which contain a nitrogen atom which is bound to the carbon of acarbonyl or a thiocarbonyl group. The term includes “alkaminocarbonyl”or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl oralkynyl groups bound to an amino group bound to a carbonyl group. Itincludes arylaminocarbonyl and arylcarbonylamino groups which includearyl or heteroaryl moieties bound to an amino group which is bound tothe carbon of a carbonyl or thiocarbonyl group. The terms“alkylaminocarbonyl,” “alkenylaminocarbonyl,” “alkynylaminocarbonyl,”“arylaminocarbonyl,” “alkylcarbonylamino,” “alkenylcarbonylamino,”“alkynylcarbonylamino,” and “arylcarbonylamino” are included in term“amide.” Amides also include urea groups (aminocarbonylamino) andcarbamates (oxycarbonylamino). The term “amide,” “amido” or“aminocarbonyl” also includes substituted moieties.

The term “carbonyl” or “carboxy” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom. Thecarbonyl can be further substituted with any moiety which allows thecompounds of the invention to perform its intended function. Forexample, carbonyl moieties may be substituted with alkyls, alkenyls,alkynyls, aryls, alkoxy, aminos, etc. Examples of moieties which containa carbonyl include aldehydes, ketones, carboxylic acids, amides, esters,anhydrides, etc.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.The term also includes substituted moieties.

The term “ether” includes compounds or moieties which contain an oxygenbonded to two different carbon atoms or heteroatoms. For example, theterm includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom which is covalentlybonded to another alkyl group. The term also includes substitutedmoieties.

The term “ester” includes compounds and moieties which contain a carbonor a heteroatom bound to an oxygen atom which is bonded to the carbon ofa carbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are asdefined above. The term also includes substituted moieties.

The term “thioether” includes compounds and moieties which contain asulfur atom bonded to two different carbon or hetero atoms. Examples ofthioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom which is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomwhich is covalently bonded to an alkynyl group. The term also includessubstituted moieties.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

The terms “polycyclyl” or “polycyclic radical” refer to two or morecyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls) in which two or more carbons are common to twoadjoining rings, e.g., the rings are “fused rings.” Rings that arejoined through non-adjacent atoms are termed “bridged” rings. Each ofthe rings of the polycycle can be substituted with such substituents asdescribed above, as for example, halogen, hydroxy, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl,arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl,arylcarbonyl, arylalkyl carbonyl, alkenylcarbonyl, aminocarbonyl,alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, cyano,amido, amino (including alkyl amino, dialkylamino, arylamino,diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or anaromatic or heteroaromatic moiety.

The term “heteroatom” includes atoms of any element other than carbon orhydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur andphosphorus.

It will be noted that the structure of some of the compounds of thisinvention includes asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers and diastereomers) are included within the scope of thisinvention, unless indicated otherwise. Such isomers can be obtained insubstantially pure form by classical separation techniques and bystereochemically controlled synthesis. Furthermore, the structures andother compounds and moieties discussed in this application also includeall tautomers thereof.

The term “isomers” refers to different compounds that have the samemolecular formula but differ in arrangement and configuration of theatoms. Moreover, the term “an optical isomer” or “a stereoisomer” refersto any of the various stereo isomeric configurations which may exist fora given compound of the present invention and includes geometricisomers. It is understood that a substituent may be attached at a chiralcenter of a carbon atom. Therefore, the invention includes enantiomers,diastereomers or racemates of the compound. “Enantiomers” are a pair ofstereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term isused to designate a racemic mixture where appropriate.“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer the stereochemistry at eachchiral carbon may be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) which they rotateplane polarized light at the wavelength of the sodium D line. Certain ofthe compounds described herein contain one or more asymmetric centersand may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)-, or (S)-. The present invention is meant toinclude all such possible isomers, including racemic mixtures, opticallypure forms and intermediate mixtures. Optically active (R)- and(S)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques. If the compound contains adouble bond, the substituent may be E or Z configuration. If thecompound contains a disubstituted cycloalkyl, the cycloalkyl substituentmay have a cis- or trans-configuration. All tautomeric forms are alsointended to be included.

The recitation of ranges of values in the present application are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range.

Any asymmetric carbon atom on the compounds of the present invention canbe present in the (R)-, (S)- or (R,S)-configuration, preferably in the(R)- or (S)-configuration. Substituents at atoms with unsaturated bondsmay, if possible, be present in cis-(Z)- or trans-(E)-form. Therefore,the compounds of the present invention can be in the form of one of thepossible isomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure geometricor optical isomers, diastereomers, racemates, for example, bychromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, the imidazolyl moiety may thusbe employed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Compounds of the present invention are either obtained in the free form,as a salt thereof, or as prodrug derivatives thereof.

The term “pharmaceutically acceptable salts” includes salts that retainthe biological effectiveness and properties of the compounds of thisinvention and, which are not biologically or otherwise undesirable. Inmany cases, the compounds of the present invention are capable offorming acid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto. Pharmaceutically acceptableacid addition salts can be formed with inorganic acids and organicacids. Inorganic acids from which salts can be derived include, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, etc. Organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptablebase addition salts can be formed with inorganic and organic bases.Inorganic bases from which salts can be derived include, for example,sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc,copper, manganese, aluminum, etc.; particularly preferred are theammonium, potassium, sodium, calcium and magnesium salts. Organic basesfrom which salts can be derived include, for example, primary,secondary, and tertiary amines, substituted amines including naturallyoccurring substituted amines, cyclic amines, basic ion exchange resins,etc., specifically such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. The pharmaceuticallyacceptable salts of the present invention can be synthesized from aparent compound, a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, non-aqueous media like ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are preferred, where practicable.Lists of additional suitable salts can be found, e.g., in Remington'sPharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa.,(1985).

When a basic group is present in the compounds of the present invention,the compounds can be converted into acid addition salts thereof, inparticular, acid addition salts with the pyridinyl moiety of thestructure, preferably pharmaceutically acceptable salts thereof. Theseare formed, with inorganic acids or organic acids. Suitable inorganicacids include but are not limited to, hydrochloric acid, sulfuric acid,a phosphoric or hydrohalic acid. Suitable organic acids include but arenot limited to, carboxylic acids, such as (C₁-C₄)alkanecarboxylic acidswhich, for example, are unsubstituted or substituted by halogen, e.g.,acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g.,oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylicacids, e.g., glycolic, lactic, malic, tartaric or citric acid, such asamino acids, e.g., aspartic or glutamic acid, organic sulfonic acids,such as (C₁-C₄)alkylsulfonic acids, e.g., methanesulfonic acid; orarylsulfonic acids which are unsubstituted or substituted, e.g., byhalogen. Preferred are salts formed with hydrochloric acid,methanesulfonic acid and maleic acid.

When an acidic group is present in the compounds of the presentinvention, the compounds can be converted into salts withpharmaceutically acceptable bases. Such salts include alkali metalsalts, like sodium, lithium and potassium salts; alkaline earth metalsalts, like calcium and magnesium salts; ammonium salts with organicbases, e.g., trimethylamine salts, diethylamine salts,tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts andN-methyl-D-glucamine salts; salts with amino acids like arginine,lysine, etc. Salts may be formed using conventional methods,advantageously in the presence of an ethereal or alcoholic solvent, suchas a lower alkanol. From the solutions of the latter, the salts may beprecipitated with ethers, e.g., diethyl ether. Resulting salts may beconverted into the free compounds by treatment with acids. These orother salts can also be used for purification of the compounds obtained.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention can also form internalsalts.

Salts of compounds of the present invention having at least onesalt-forming group may be prepared in a manner known per se. Forexample, salts of compounds of the present invention having acid groupsmay be formed, for example, by treating the compounds with metalcompounds, such as alkali metal salts of suitable organic carboxylicacids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkalimetal or alkaline earth metal compounds, such as the correspondinghydroxides, carbonates or hydrogen carbonates, such as sodium orpotassium hydroxide, carbonate or hydrogen carbonate, with correspondingcalcium compounds or with ammonia or a suitable organic amine,stoichiometric amounts or only a small excess of the salt-forming agentpreferably being used. Acid addition salts of compounds of the presentinvention are obtained in customary manner, e.g. by treating thecompounds with an acid or a suitable anion exchange reagent. Internalsalts of compounds of the present invention containing acid and basicsalt-forming groups, e.g. a free carboxy group and a free amino group,may be formed, e.g. by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g. with weak bases, or bytreatment with ion exchangers.

Salts can be converted in customary manner into the free compounds;metal and ammonium salts can be converted, for example, by treatmentwith suitable acids, and acid addition salts, for example, by treatmentwith a suitable basic agent.

The present invention includes all pharmaceutically acceptableisotopically-labeled compounds of the invention, i.e. Agents of theInvention, wherein (1) one or more atoms are replaced by atoms havingthe same atomic number, but an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature, and/or (2) theisotopic ratio of one or more atoms is different from the naturallyoccurring ratio.

Examples of isotopes suitable for inclusion in the compounds of theinvention comprises isotopes of hydrogen, such as ²H and ³H, carbon,such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labeled Agents of the Invention, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled Agents of the Invention can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

The present invention also provides prodrug moieties of the compounds ofthe present invention that convert in vivo to the compounds of thepresent invention. A prodrug moiety is an active or inactive compoundthat is modified chemically through in vivo physiological action, suchas hydrolysis, metabolism, etc., into a compound of this inventionfollowing administration of the prodrug to a subject. The term “prodrugmoiety” includes moieties which can be metabolized in vivo to a hydroxygroup and moieties which may advantageously remain esterified in vivo.Preferably, the prodrugs moieties are metabolized in vivo by esterasesor by other mechanisms to hydroxy groups or other advantageous groups.Examples of prodrugs and their uses are well known in the art (See,e.g., Berge et al. (1977) “Pharmaceutical Salts” J. Pharm. Sci.66:1-19). The prodrugs can be prepared in situ during the finalisolation and purification of the compounds, or by separately reactingthe purified compound in its free acid form or hydroxy with a suitableesterifying agent. Hydroxy groups can be converted into esters viatreatment with a carboxylic acid. Examples of prodrug moieties includesubstituted and unsubstituted, branch or unbranched lower alkyl estermoieties, (e.g., propionoic acid esters), lower alkenyl esters, di-loweralkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester),acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxylower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenylester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g.,with methyl, halo, or methoxy substituents) aryl and aryl-lower alkylesters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxyamides. Preferred prodrug moieties are propionoic acid esters and acylesters.

The suitability and techniques involved in making and using prodrugs arewell known by those skilled in the art. Prodrugs can be conceptuallydivided into two non-exclusive categories, bioprecursor prodrugs andcarrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31-32(Ed. Wermuth, Academic Press, San Diego, Calif., 2001). Generally,bioprecursor prodrugs are compounds are inactive or have low activitycompared to the corresponding active drug compound that contains one ormore protective groups and are converted to an active form by metabolismor solvolysis. Both the active drug form and any released metabolicproducts should have acceptably low toxicity. Typically, the formationof active drug compound involves a metabolic process or reaction that isone of the follow types:

1. Oxidative reactions, such as oxidation of alcohol, carbonyl, and acidfunctions, hydroxylation of aliphatic carbons, hydroxylation ofalicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation ofcarbon-carbon double bonds, oxidation of nitrogen-containing functionalgroups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-dealkylation, oxidative O- and S-dealkylation, oxidative deamination,as well as other oxidative reactions.

2. Reductive reactions, such as reduction of carbonyl groups, reductionof alcoholic groups and carbon-carbon double bonds, reduction ofnitrogen-containing functions groups, and other reduction reactions.

3. Reactions without change in the state of oxidation, such ashydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogensingle bonds, hydrolytic cleavage of non-aromatic heterocycles,hydration and dehydration at multiple bonds, new atomic linkagesresulting from dehydration reactions, hydrolytic dehalogenation, removalof hydrogen halide molecule, and other such reactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. See, Cheng et al., US20040077595,incorporated herein by reference. Such carrier prodrugs are oftenadvantageous for orally administered drugs. Carrier prodrugs can, forexample, be used to improve one or more of the following properties:increased lipophilicity, increased duration of pharmacological effects,increased site-specificity, decreased toxicity and adverse reactions,and/or improvement in drug formulation (e.g., stability, watersolubility, suppression of an undesirable organoleptic or physiochemicalproperty). For example, lipophilicity can be increased by esterificationof hydroxy groups with lipophilic carboxylic acids, or of carboxylicacid groups with alcohols, e.g., aliphatic alcohols. Wermuth, ThePractice of Medicinal Chemistry, Ch. 31-32, Ed. Werriuth, AcademicPress, San Diego, Calif., 2001.

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyland O-acyl derivatives of thiols, alcohols or phenols, wherein acyl hasa meaning as defined herein. Preferred are pharmaceutically acceptableester derivatives convertible by solvolysis under physiologicalconditions to the parent carboxylic acid, e.g., lower alkyl esters,cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- ordi-substituted lower alkyl esters, such as the ω-(amino, mono- ordi-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters,the α-(lower alkanoyloxy, lower alkoxycarbonyl or di-loweralkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethylester, etc. conventionally used in the art. In addition, amines havebeen masked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugs containing anacidic NH group, such as imidazole, imide, indole, etc., have beenmasked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

In view of the close relationship between the compounds, the compoundsin the form of their salts and the prodrugs, any reference to thecompounds of the present invention is to be understood as referring alsoto the corresponding prodrugs of the compounds of the present invention,as appropriate and expedient.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization.

Compounds of the present invention are prepared from commonly availablecompounds using procedures known to those skilled in the art, includingany one or more of the following conditions without limitation:

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group”, unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such asJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press,London and New York 1973, in T. W. Greene and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, Third edition, Wiley, New York 1999.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known per se into the individual isomers;diastereoisomers can be separated, for example, by partitioning betweenpolyphasic solvent mixtures, recrystallisation and/or chromatographicseparation, for example over silica gel or by e.g. medium pressureliquid chromatography over a reversed phase column, and racemates can beseparated, for example, by the formation of salts with optically puresalt-forming reagents and separation of the mixture of diastereoisomersso obtainable, for example by means of fractional crystallisation, or bychromatography over optically active column materials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-) crystallization, etc.

The following applies in general to all processes mentioned hereinbefore and hereinafter.

All the above-mentioned process steps can be carried out under reactionconditions that are known per se, including those mentionedspecifically, in the absence or, customarily, in the presence ofsolvents or diluents, including, for example, solvents or diluents thatare inert towards the reagents used and dissolve them, in the absence orpresence of catalysts, condensation or neutralizing agents, for exampleion exchangers, such as cation exchangers, e.g. in the H+ form,depending on the nature of the reaction and/or of the reactants atreduced, normal or elevated temperature, for example in a temperaturerange of from about −100° C. to about 190° C., including, for example,from approximately −80° C. to approximately 150° C., for example at from−80 to −60° C., at room temperature, at from −20 to 40° C. or at refluxtemperature, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane,liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, suchas methanol, ethanol or 1- or 2-propanol, nitriles, such asacetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, or mixtures of those solvents, for example aqueoussolutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4^(th) Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21).

Generally, enantiomers of the compounds of the present invention can beprepared by methods known to those skilled in the art to resolve racemicmixtures, such as by formation and recrystallization of diastereomericsalts or by chiral chromotagraphy or HPLC separation utilizing chiralstationery phases.

In starting compounds and intermediates which are converted to thecompounds of the invention in a manner described herein, functionalgroups present, such as amino, thiol, carboxyl and hydroxy groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected amino, thiol, carboxyl andhydroxy groups are those that can be converted under mild conditionsinto free amino thiol, carboxyl and hydroxy groups without the molecularframework being destroyed or other undesired side reactions takingplace.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxy group, aminogroup, etc.), the structure and stability of the molecule of which thesubstituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, e.g., in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London, N.Y. (1973); andGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wileyand Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably, such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents, respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures, preferably ator near the boiling point of the solvents used, and at atmospheric orsuper-atmospheric pressure. The preferred solvents, catalysts andreaction conditions are set forth in the appended illustrative Examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Abbreviations

ATP: adenosine 5′-triphosphate BINAP: racemic 2,2′-bis(diphenylphosphino)-1,1′- binaphthyl BOC: tertiary butyl carboxy br:broad bs: broad singlet calcd: calculated d: doublet DAST:(diethylamino)sulfur trifluoride dd: doublet of doublets DCM:dichloromethane DIEA: diethylisopropylamine DME: 1,4-dimethoxyethaneDMF: N,N-dimethylformamide DMSO: dimethylsulfoxide DPPA:diphenylphosphorylazide DTT: dithiothreitol EDTA: ethylenediaminetetraacetic acid ESI: electrospray ionization EtOAc: ethyl acetate h:hour(s) HATU: O-(7-azobenzotriazol-1-yl)-1,1,3,3- HOBt:1-hydroxy-7-azabenzotriazole tetramethyluroniumhexafluorophosphate HPLC:high pressure liquid chromatography LCMS: liquid chromatography and massspectrometry MeOD: methanol-d4 MeOH: methanol MS: mass spectrometry m:multiplet min: minutes m/z: mass to charge ratio n.d.: not determinedNMR: nuclear magnetic resonance ppm: parts per million Pr: propyl PyBOP:benzotriazol-1-yloxy rt: room temperatureTripyrrolidinophosphoniumhexafluorophosphate s: singlet t: triplet TFA:trifluoroacetic acid THF: tetrahydrofuran TLC: thin layer chromatographyTris•HCl: aminotris(hydroxymethyl)methane hydrochloride

Methods for Synthesizing Compounds of the Invention

The compounds of the invention can be synthesized using the methodsdescribed in the following schemes, examples, and by using artrecognized techniques. All compounds described herein are included inthe invention as compounds. Compounds of the invention may besynthesized according to at least one of the methods described inschemes 1-7.

In step 1, the appropriate hydrazine derivative 2 is heated with3-acetylpyridine derivative 3 in a solvent, e.g. ethanol, resulting inthe formation of the corresponding hydrazone, which upon addition of anacid, e.g. hydrogen chloride, undergoes a Fisher reaction to give indole4. Pyridine 3 can be conveniently prepared from nicotinic acid, viaformation of the Weinreb amide and subsequent addition of theappropriate Grignard reagent, e.g. n-propyl magnesium bromide. In step2, indole 4 is deprotonated with a strong base, such as potassiumhexamethyldisilamide, and the resulting anion is trapped with theappropriate electrophilic reagent, e.g. an acid chloride, achloroformate, an alkyl bromide, an alkyl chloride or an alkyl iodide,to give indole 5. Appropriate transformation of R8 in 5 leads to furtheranalogs. For example, if R8 contains an ester, the ester can behydrolyzed to the corresponding carboxylic acid. In another example, ifR8 contains a nitrile, the nitrile can be reacted with azide to give thecorresponding tetrazole.

In step 1, the appropriate hydrazine derivative 2 is heated with3-acetylpyridine 6 in a solvent, e.g. ethanol, resulting in theformation of the corresponding hydrazone 7. In step 2, 7 is heated,neat, with polyphosphoric acid, preferably between 160° C. and 220° C.,to give indole 8. In step 3, indole 4 is deprotonated with a strongbase, e.g. potassium hexamethyldisilamide, and the resulting anion istrapped with the appropriate electrophilic reagent, e.g. an acidchloride, a chloroformate, an alpha,beta-unsturated ketone or ester, analkyl bromide, an alkyl chloride or an alkyl iodide, to give indole 9.Appropriate transformation of R8 in 9 leads to further analogs. Forexample, if R8 contains an ester, the ester can be hydrolyzed to thecorresponding carboxylic acid. In another example, if R8 contains anitrile, the nitrile can be reacted with azide to give the correspondingtetrazole.

In step 1, the appropriate aniline derivative 10 is coupled withnicotinyl chloride in the presence of an amine base, e.g.diisopropylethylamine, to give amide 12. In step 2, heating of 12 in thepresence of a strong base, e.g. sodium hydride, gives indole 13. In step3, indole 13 is deprotonated with a strong base, e.g. sodium hydride,and the resulting anion is trapped with the appropriate electrophilicreagent, e.g. methyl iodide, to give indole 14.

Step 1 involves the reaction of an iodoaniline derivative 15 andacetylene derivative 16 in the presence of palladium salts, e.g.PdCl₂(PPh₃)₂, copper salts, preferably copper iodide, in an aminesolvent, preferably triethylamine, to give alkyne 17. In step 2,treatment of aniline 17 with a base, e.g. potassium tert-butoxide, in apolar solvent, preferably N-methylpyrrolidinone, gives indole 18. Instep 3, indole 18 is deprotonated with a strong base, e.g. sodiumhydride, and the resulting anion is trapped with the appropriateelectrophilic reagent, e.g. an alkyl chloride, or analpha,beta-unsturated ketone to give indole 19. Optionally, indole 19can be reacted with chlorosulfonyl isocyanate, followed withdimethylformamide, as in step 4, to give indole 20. Appropriatetransformations of R8 in 19 lead to further analogs. For example, if R8contains an ester, the ester can be hydrolyzed to the correspondingcarboxylic acid.

Step 1 involves the reaction of an iodoaniline derivative 15 andacetylene derivative 16 in the presence of palladium salts, e.g.PdCl₂(PPh₃)₂, copper salts, e.g. copper iodide, in an amine solvent,e.g. triethylamine, to give alkyne 17. In step 2, treatment of aniline17 with a base, e.g. potassium tert-butoxide, in a polar solvent, e.g.N-methylpyrrolidinone, gives indole 18. In step 3, indole 18 can bereacted with chlorosulfonyl isocyanate, followed with dimethylformamide,to give indole 21. In step 4, indole 21 is deprotonated with a strongbase, e.g. sodium hydride, and the resulting anion is trapped with theappropriate electrophilic reagent, e.g. methyl iodide to give indole 22.

In step 1, the appropriate N-Boc-2-indole boronic acid 23 is reactedwith the appropriate 3-bromopyridine 24 in the presence of palladiumsalts, e.g. Pd₂ dba₃, ligands, e.g. s-Phos, and a base, e.g. potassiumphosphate, in an organic solvent, e.g. toluene, to give indole 25. Instep 2, the carbamate is cleaved, e.g. using trifluoroacetic acid orsilica gel. In step 3, indole 18 is deprotonated with a strong base,e.g. sodium hydride, and the resulting anion is trapped with theappropriate electrophilic reagent, e.g. methyl iodide to give indole 19.Alternatively, indole 18 can be heated with dimethylcarbonate in thepresence of a base, e.g. potassium carbonate, to give indole 19, whereR8 is methyl. Optionally, indole 19 can be reacted with chlorosulfonylisocyanate, followed with dimethylformamide, as in step 4, to giveindole 20. Appropriate transformations of R6 and R⁷ in 19 or 20 lead tofurther analogs.

In step 1, the appropriate N-methyl-2-indole boronic acid 26 is reactedwith the appropriate heterocycle 24 in the presence of palladium salts,e.g. Pd₂ dba₃, ligands, e.g. s-Phos, and a base, e.g. potassiumphosphate, in an organic solvent, e.g. toluene, to give indole 27.Optionally, indole 27 can be reacted with chlorosulfonyl isocyanate,followed with dimethylformamide, as in step 2, to give indole 28.Appropriate transformations of R⁶ and R⁷ in 27 or 28 lead to furtheranalogs.

Methods of the Invention

The invention pertains, at least in part, to methods for treating asubject for a disorder or disease, by administering to a subject atherapeutically effective amount of a compound of Formula I:

wherein:

R^(1a), R^(2a), R^(3a), and R^(4a) are each independently hydrogen,halogen, cyano, hydroxy, alkoxy, alkyl, alkenyl, or alkoxycarbonyl;

R^(5a) is hydrogen halogen, cyano, alkyl, alkenyl, arylalkyl,heteroarylalkyl, aminocarbonyl, alkylaminocarbonyl, carboxylate,alkoxycarbonyl, heterocyclylcarbonyl, aryl, or heteroaryl;

R^(6a) and R^(7a) are each independently hydrogen, halogen, hydroxy,alkoxy, amino, alkyl, sulfonyl, —O-sulfonyl, alkylamino, heterocyclyl,aminocarbonyl, carboxylate, or alkoxycarbonyl;

R^(8a) is hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkoxycarbonyl,sulfonyl, aroyl, aryl, or heteroaryl; and pharmaceutically acceptablesalts, polymorphs, rotamers, prodrugs, enantiomers, hydrates, andsolvates thereof, with the proviso that at least one of R^(1a)-R^(8a) isother than hydrogen; and when R^(5a) is cyano or lower alkyl optionallysubstituted with cyano, —C(O)-piperidine, amino, alkylamino,dialkylamino, carboxylate, alkoxycarbonyl, aminocarbonyl, orheterocyclyl, then at least one of R^(1a)-R^(4a) and R^(6a)-R^(8a) isother than hydrogen; and when R^(7a) is imidazolyl, then at least one ofR^(1a)-R^(6a) and R^(8a) is other than hydrogen; and when R^(8a) isalkyl, arylalkyl or alkoxycarbonyl, then at least one of R^(1a)-R^(7a)is other than hydrogen; and when R^(5a) is lower alkyl and R^(8a) isalkyl substituted with carboxylate or PO₃R²¹R²² wherein R²¹ and R²² areeach independently hydrogen or lower alkyl, then at least one ofR^(1a)-R^(4a) and R^(6a) and R^(7a) is other than hydrogen; and whenR^(3a) is halogen and R^(5a) and R^(8a) are independently lower alkyloptionally substituted with carboxylate, alkoxycarbonyl, or—C(O)-piperidine, then at least one of R^(1a), R^(2a)R^(4a), R^(6a) andR^(7a) is other than hydrogen; and when R^(3a) is halogen or lower alkyland R^(5a) is lower alkyl substituted with dialkylamino,dialkylaminocarbonyl, carboxylate, alkoxycarbonyl or aminocarbonyl, thenat least one of R^(1a), R^(2a), R^(4a) and R^(6a)-R^(8a) is other thanhydrogen; and when R^(2a) and R^(3a) are each alkoxy and R^(5a) iscyano, then at least one of R^(1a), R^(4a), and R^(6a)-R^(8a) is otherthan hydrogen; and when R^(3a) is alkyl substituted with aroyl, and R⁵and R⁸ are each independently hydrogen or lower alkyl, then at least oneof R^(1a), R^(2a), and R^(4a) is other than hydrogen, such that saiddisorder or disease in said subject is treated.

In one embodiment, the invention pertains, at least in part, to methodsfor treating a subject for a disorder or disease, by administering to asubject a therapeutically effective amount of a compound of Formula II:

wherein:

R^(2q) is hydrogen or halogen;

R^(3q) is hydrogen, halogen, or cyano;

R^(5q) is hydrogen, alkyl, or cyano;

R^(7q) hydrogen, halogen, alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl,—NR′—SO₂-alkyl, —NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl, —NR′—C(O)—O-alkyl,haloalkyl, or alkyl optionally substituted with heterocyclyl,—NR′—SO₂-alkyl, —NR′—SO₂-haloalkyl, NR′—C(O)-alkyl,NR′—C(O)-heterocyclyl, —NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl;

R^(8q) is hydrogen, alkyl, hydroxyalkyl, -alkyl-OC(O)-alkyl,carboxylate, alkoxycarbonyl, or arylalkyl substituted with alkyl, oraroyl substituted with cyano and/or alkyl, or -alkyl-O-aryl substitutedwith alkoxycarbonyl;

each R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl andpharmaceutically acceptable salts, polymorphs, rotamers, prodrugs,enantiomers, hydrates, and solvates thereof, with the proviso that atleast one of R^(2q), R^(3q), R^(5q), R^(7q) and R^(8q) is other thanhydrogen, such that said disorder or disease in said subject is treated.

In another embodiment, the invention pertains, at least in part, tomethods for treating a subject for a disorder or disease, byadministering to a subject a therapeutically effective amount of acompound of Formulae III or IV, and pharmaceutically acceptable salts,polymorphs, rotamers, prodrugs, enantiomers, hydrates, and solvatesthereof, such that said disorder or disease in said subject is treated.

The term “disorder” or “disease” includes any pathological condition,derangement, or abnormality of function of a part, organ, or system ofan organism resulting from various causes, such as infection, geneticdefect, or environmental stress, and characterized by an identifiablegroup of signs or symptoms; and any morbid physical or mental state. SeeDorland's Illustrated Medical Dictionary, (W.B. Saunders Co. 27th ed.1988).

In another embodiment, the disorder or disease is a disease selectedfrom, hypokalemia, hypertension, Conn's disease, renal failure, inparticular, chronic renal failure, restenosis, atherosclerosis, syndromeX, obesity, nephropathy, post-myocardial infarction, coronary heartdiseases, increased formation of collagen, fibrosis and remodelingfollowing hypertension and endothelial dysfunction, cardiovasculardiseases, renal dysfunction, liver diseases, cerebrovascular diseases,vascular diseases, retinopathy, neuropathy, insulinopathy, edema,endothelial dysfunction, baroreceptor dysfunction, migraine headaches,heart failure such as congestive heart failure, arrhythmia, diastolicdysfunction, left ventricular diastolic dysfunction, diastolic heartfailure, impaired diastolic filling, systolic dysfunction, ischemia,hypertropic cardiomyopathy, sudden cardiac death, myocardial andvascular fibrosis, impaired arterial compliance, myocardial necroticlesions, vascular damage, myocardial infarction, left ventricularhypertrophy, decreased ejection fraction, cardiac lesions, vascular wallhypertrophy, endothelial thickening, or fibrinoid necrosis of coronaryarteries.

The invention also pertains, at least in part, to methods of inhibitingaldosterone synthase activity in a subject, by administering to asubject a therapeutically effective amount of a compound of Formula I:

wherein:

R^(1a), R^(2a), R^(3a), and R^(4a) are each independently hydrogen,halogen, cyano, hydroxy, alkoxy, alkyl, alkenyl, or alkoxycarbonyl;

R^(5a) is hydrogen halogen, cyano, alkyl, alkenyl, arylalkyl,heteroarylalkyl, aminocarbonyl, alkylaminocarbonyl, carboxylate,alkoxycarbonyl, heterocyclylcarbonyl, aryl, or heteroaryl;

R^(6a) and R^(7a) are each independently hydrogen, halogen, hydroxy,alkoxy, amino, alkyl, sulfonyl, —O-sulfonyl, alkylamino, heterocyclyl,aminocarbonyl, carboxylate, or alkoxycarbonyl;

R^(8a) is hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkoxycarbonyl,sulfonyl, aroyl, aryl, or heteroaryl; and pharmaceutically acceptablesalts, polymorphs, rotamers, prodrugs, enantiomers, hydrates, andsolvates thereof, such that aldosterone synthase activity is inhibited.

The invention also pertains, at least in part, to methods of inhibitingaldosterone synthase activity in a subject, by administering to asubject a therapeutically effective amount of a compound of Formula II:

wherein:

R^(2q) is hydrogen or halogen;

R^(3q) is hydrogen, halogen, or cyano;

R^(5q) is hydrogen, alkyl, or cyano;

R^(7q) is hydrogen, halogen, alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl,—NR′—SO₂-alkyl, —NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl, —NR′—C(O)—O-alkyl,haloalkyl, or alkyl optionally substituted with heterocyclyl,—NR′—SO₂-alkyl, —NR′—SO₂-haloalkyl, NR′—C(O)-alkyl,NR′—C(O)-heterocyclyl, —NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl;

R^(8q) is hydrogen, alkyl, hydroxyalkyl, -alkyl-OC(O)-alkyl,carboxylate, alkoxycarbonyl, or arylalkyl substituted with alkyl, oraroyl substituted with cyano and/or alkyl, or -alkyl-O-aryl substitutedwith alkoxycarbonyl;

each R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl, andpharmaceutically acceptable salts, polymorphs, rotamers, prodrugs,enantiomers, hydrates, and solvates thereof, such that aldosteronesynthase activity is inhibited.

In one embodiment, the invention pertains, at least in part, to methodsof inhibiting aldosterone synthase activity in a subject, byadministering to a subject a therapeutically effective amount of acompound of Formulae III or IV, such that aldosterone synthase activityis inhibited.

Another embodiment of the present invention includes methods fortreating an aldosterone synthase associated state, by administering to asubject a therapeutically effective amount of a compound of Formula I:

wherein:

R^(1a), R^(2a), R^(3a) and R^(4a) are each independently hydrogen,halogen, cyano, hydroxy, alkoxy, alkyl, alkenyl, or alkoxycarbonyl;

R^(5a) is hydrogen halogen, cyano, alkyl, alkenyl, arylalkyl,heteroarylalkyl, aminocarbonyl, alkylaminocarbonyl, carboxylate,alkoxycarbonyl, heterocyclylcarbonyl, aryl, or heteroaryl;

R^(6a) and R^(7a) are each independently hydrogen, halogen, hydroxy,alkoxy, amino, alkyl, sulfonyl, —O-sulfonyl, alkylamino, heterocyclyl,aminocarbonyl, carboxylate, or alkoxycarbonyl;

R^(8a) is hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkoxycarbonyl,sulfonyl, aroyl, aryl, or heteroaryl; and pharmaceutically acceptablesalts, polymorphs, rotamers, prodrugs, enantiomers, hydrates, andsolvates thereof, such that said aldosterone synthase associated statein said subject is treated.

Yet another embodiment of the present invention includes methods oftreating an aldosterone synthase associated state, by administering to asubject a therapeutically effective amount of a compound of Formula II:

wherein:

R^(2q) is hydrogen or halogen;

R^(3q) is hydrogen, halogen, or cyano;

R^(5q) is hydrogen, alkyl, or cyano;

R^(7q) is hydrogen, halogen, alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl,—NR′—SO₂-alkyl, —NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl, —NR′—C(O)—O-alkyl,haloalkyl, or alkyl optionally substituted with heterocyclyl,—NR′—SO₂-alkyl, —NR′—SO₂-haloalkyl, NR′—C(O)-alkyl,NR′—C(O)-heterocyclyl, —NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl;

R^(8q) is hydrogen, alkyl, hydroxyalkyl, -alkyl-OC(O)-alkyl,carboxylate, alkoxycarbonyl, or arylalkyl substituted with alkyl, oraroyl substituted with cyano and/or alkyl, or -alkyl-O-aryl substitutedwith alkoxycarbonyl;

each R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl, andpharmaceutically acceptable salts, polymorphs, rotamers, prodrugs,enantiomers, hydrates, and solvates thereof, such that said aldosteronesynthase associated state in said subject is treated.

Yet another embodiment of the present invention includes methods oftreating an aldosterone synthase associated state, by administering to asubject a therapeutically effective amount of a compound of Formula IIIor IV, such that said aldosterone synthase associated state in saidsubject is treated.

The term “aldosterone synthase associated state” refers to a state,disease, or disorder which can be treated by the modulation, (e.g.,inhibition) of aldosterone synthase. Aldosterone synthase is amitcohcondrial cytochrome P450 enzyme catalyzing the last step ofaldosterone production in the adrenal cortex, i.e., the conversion of11-deoxycorticosterone to aldosterone. Aldosterone synthase has beendemonstrated to be expressed in all cardiovascular tissues such asheart, umbilical cord, mesenteric and pulmonary arteries, aorta,endothelium and vascular cells. Moreover, the expression of aldosteronesynthase is closely correlated with aldosterone production in cells. Ithas been observed that elevations of aldosterone activity inducesdifferent diseases such as congestive heart failure, myocardialfibrosis, ventricular arrhythmia and other adverse effects, etc.

Examples of aldosterone synthase associated states include hypokalemia,hypertension, Conn's disease, renal failure, in particular, chronicrenal failure, restenosis, atherosclerosis, syndrome X, obesity,nephropathy, post-myocardial infarction, coronary heart diseases,increased formation of collagen, fibrosis and remodeling followinghypertension and endothelial dysfunction, cardiovascular diseases, renaldysfunction, liver diseases, cerebrovascular diseases, vasculardiseases, retinopathy, neuropathy, insulinopathy, edema, endothelialdysfunction, baroreceptor dysfunction, migraine headaches, heart failuresuch as congestive heart failure, arrhythmia, diastolic dysfunction,left ventricular diastolic dysfunction, diastolic heart failure,impaired diastolic filling, systolic dysfunction, ischemia, hypertropiccardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis,impaired arterial compliance, myocardial necrotic lesions, vasculardamage, myocardial infarction, left ventricular hypertrophy, decreasedejection fraction, cardiac lesions, vascular wall hypertrophy,endothelial thickening, and fibrinoid necrosis of coronary arteries.

In one embodiment, the aldosterone synthase associated state ischaracterized by abnormal activity of aldosterone synthase and/orabnormal expression of aldosterone synthase.

The term “abnormal” includes an activity or feature which differs from anormal activity or feature.

The term “abnormal activity” includes an activity which differs from theactivity of the wild-type or native gene or protein, or which differsfrom the activity of the gene or protein in a healthy subject. Theabnormal activity can be stronger or weaker than the normal activity.

In one embodiment, the “abnormal activity” includes the abnormal (eitherover- or under-) production of mRNA transcribed from a gene. In anotherembodiment, the “abnormal activity” includes the abnormal (either over-or under-) production of polypeptide from a gene. In another embodiment,the abnormal activity refers to a level of a mRNA or polypeptide that isdifferent from a normal level of said mRNA or polypeptide by about 15%,about 25%, about 35%, about 50%, about 65%, about 85%, about 100% orgreater. Preferably, the abnormal level of the mRNA or polypeptide canbe either higher or lower than the normal level of said mRNA orpolypeptide. Yet in another embodiment, the abnormal activity refers tofunctional activity of a protein that is different from a normalactivity of the wild-type protein. Preferably, the abnormal activity canbe stronger or weaker than the normal activity. Preferably, the abnormalactivity is due to the mutations in the corresponding gene, and themutations can be in the coding region of the gene or non-coding regionssuch as transcriptional promoter regions. The mutations can besubstitutions, deletions, insertions.

The compounds of the present invention, as aldosterone synthaseinhibiting compounds, are useful for treatment of a disorder or diseasemediated by aldosterone synthase or responsive to inhibition ofaldosterone synthase. In particular, the compounds of the presentinvention are useful for treatment of a aldosterone synthase associatedstate including hypokalemia, hypertension, Conn's disease, renalfailure, in particular, chronic renal failure, restenosis,atherosclerosis, syndrome X, obesity, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction, cardiovascular diseases, renal dysfunction, liver diseases,cerebrovascular diseases, vascular diseases, retinopathy, neuropathy,insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction,migraine headaches, heart failure such as congestive heart failure,arrhythmia, diastolic dysfunction, left ventricular diastolicdysfunction, diastolic heart failure, impaired diastolic filling,systolic dysfunction, ischemia, hypertropic cardiomyopathy, suddencardiac death, myocardial and vascular fibrosis, impaired arterialcompliance, myocardial necrotic lesions, vascular damage, myocardialinfarction, left ventricular hypertrophy, decreased ejection fraction,cardiac lesions, vascular wall hypertrophy, endothelial thickening, andfibrinoid necrosis of coronary arteries.

The term “aldosterone synthase inhibiting compound” includes compoundswhich reduce the activity of aldosterone synthase, e.g., the ability ofaldosterone synthase to synthesize aldosterone, in vivo or in vitro. Inone embodiment, the aldosterone synthase inhibiting compounds arealdosterone synthesis inhibiting compounds.

The term “inhibition” or “inhibiting” includes the reduction orsuppression of a given condition, symptom, or disorder, or disease, or asignificant decrease in the baseline activity of a biological activityor process. In one embodiment, the condition or symptom or disorder ordisease is mediated by aldosterone synthase activity. In anotherembodiment, the condition or symptom or disorder or disease isassociated with the abnormal activity of aldosterone synthase, or thecondition or symptom or disorder or disease is associated with theabnormal expression of aldosterone synthase.

The term “subject” includes animals (e.g., mammals). A subject alsorefers to for example, primates (e.g., humans, including males andfemales), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice,fish, birds, etc.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviate, inhibit,prevent and/or ameliorate a condition, or a disorder or a disease (i)mediated by aldosterone synthase, or (ii) associated with aldosteronesynthase activity, or (iii) characterized by abnormal activity ofaldosterone synthase; or (2) reduce or inhibit the activity ofaldosterone synthase; or (3) reduce or inhibit the expression ofaldosterone synthase. In another non-limiting embodiment, the term “atherapeutically effective amount” refers to the amount of the compoundof the present invention that, when administered to a cell, or a tissue,or a non-cellular biological material, or a medium, is effective to atleast partially reduce or inhibit the activity of aldosterone synthase;or at least partially reduce or inhibit the expression of aldosteronesynthase.

The effective amount can vary depending on such factors as the size andweight of the subject, the type of illness, or the particular organiccompound. For example, the choice of the organic compound can affectwhat constitutes an “effective amount.” One of ordinary skill in the artwould be able to study the aforementioned factors and make thedetermination regarding the effective amount of the organic compoundwithout undue experimentation.

The term “treating” or “treatment” of any disease or disorder includescuring as well as ameliorating at least one symptom of the state,disease, or disorder (e.g., the aldosterone synthase associated state).The term may also include alleviating or ameliorating at least onephysical parameter including those which may not be discernible by thepatient; or modulating the disease or disorder, either physically,(e.g., stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. The terms may alsoinclude preventing or delaying the onset or development or progressionof the disease or disorder.

A further embodiment includes methods for treating an aldosteronesynthase associated disorder or disease in a subject by administering toa subject an effective amount of a compound of the invention (e.g., acompound of Formulae I-IV, or a compound otherwise described herein) incombination with a second agent, such that the subject is treated forsaid aldosterone synthase associated disorder.

The disorder or disease may be characterized by an abnormal activity ofaldosterone synthase or abnormal expression of aldosterone synthase.

In one embodiment the disorder or disease includes but is not limited tohypokalemia, hypertension, Conn's disease, renal failure, in particular,chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity,nephropathy, post-myocardial infarction, coronary heart diseases,increased formation of collagen, fibrosis and remodeling followinghypertension and endothelial dysfunction, cardiovascular diseases, renaldysfunction, liver diseases, cerebrovascular diseases, vasculardiseases, retinopathy, neuropathy, insulinopathy, edema, endothelialdysfunction, baroreceptor dysfunction, migraine headaches, heart failuresuch as congestive heart failure, arrhythmia, diastolic dysfunction,left ventricular diastolic dysfunction, diastolic heart failure,impaired diastolic filling, systolic dysfunction, ischemia, hypertropiccardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis,impaired arterial compliance, myocardial necrotic lesions, vasculardamage, myocardial infarction, left ventricular hypertrophy, decreasedejection fraction, cardiac lesions, vascular wall hypertrophy,endothelial thickening, and fibrinoid necrosis of coronary arteries.

In one embodiment, the invention pertains, at least in part, to methodsfor treating a subject for heart failure, congestive heart failure,arrhythmia, diastolic dysfunction, left ventricular diastolicdysfunction, diastolic heart failure, impaired diastolic filling,systolic dysfunction, ischemia, hypertropic cardiomyopathy, suddencardiac death, myocardial and vascular fibrosis, impaired arterialcompliance, myocardial necrotic lesions, vascular damage, myocardialinfarction, left ventricular hypertrophy, decreased ejection fraction,cardiac lesions, vascular wall hypertrophy, endothelial thickening,fibrinoid necrosis of coronary arteries, renal dysfunction, liverdiseases, cerebrovascular diseases, vascular diseases, retinopathy,neuropathy, insulinopathy, edema, endothelial dysfunction, baroreceptordysfunction, migraine headaches, or hypertension, comprisingadministering to said subject an effective amount of a compound ofFormula I:

wherein:

R^(1a), R^(2a), R^(3a) and R^(4a) are each independently hydrogen,halogen, cyano, hydroxy, alkoxy, alkyl, alkenyl, or alkoxycarbonyl;

R^(5a) is hydrogen halogen, cyano, alkyl, alkenyl, arylalkyl,heteroarylalkyl, aminocarbonyl, alkylaminocarbonyl, carboxylate,alkoxycarbonyl, heterocyclylcarbonyl, aryl, or heteroaryl;

R^(6a) and R^(7a) are each independently hydrogen, halogen, hydroxy,alkoxy, amino, alkyl, sulfonyl, —O-sulfonyl, alkylamino, heterocyclyl,aminocarbonyl, carboxylate, or alkoxycarbonyl;

R^(8a) is hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkoxycarbonyl,sulfonyl, aroyl, aryl, or heteroaryl; and pharmaceutically acceptablesalts, polymorphs, rotamers, prodrugs, enantiomers, hydrates, andsolvates thereof, such that said subject is treated.

In another embodiment, the invention pertains, at least in part, tomethods for treating a subject for heart failure, congestive heartfailure, arrhythmia, diastolic dysfunction, left ventricular diastolicdysfunction, diastolic heart failure, impaired diastolic filling,systolic dysfunction, ischemia, hypertropic cardiomyopathy, suddencardiac death, myocardial and vascular fibrosis, impaired arterialcompliance, myocardial necrotic lesions, vascular damage, myocardialinfarction, left ventricular hypertrophy, decreased ejection fraction,cardiac lesions, vascular wall hypertrophy, endothelial thickening,fibrinoid necrosis of coronary arteries, renal dysfunction, liverdiseases, cerebrovascular diseases, vascular diseases, retinopathy,neuropathy, insulinopathy, edema, endothelial dysfunction, baroreceptordysfunction, migraine headaches, or hypertension, comprisingadministering to said subject an effective amount of a compound ofFormula II:

wherein:

R^(2q) is hydrogen or halogen;

R^(3q) is hydrogen, halogen, or cyano;

R^(5q) is hydrogen, alkyl, or cyano;

R^(7q) is hydrogen, halogen, alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl,—NR′—SO₂-alkyl, —NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl, —NR′—C(O)—O-alkyl,haloalkyl, or alkyl optionally substituted with heterocyclyl,—NR′—SO₂-alkyl, —NR′—SO₂-haloalkyl, NR′—C(O)-alkyl,NR′—C(O)-heterocyclyl, —NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl;

R^(8q) is hydrogen, alkyl, hydroxyalkyl, -alkyl-OC(O)-alkyl,carboxylate, alkoxycarbonyl, or arylalkyl substituted with alkyl, oraroyl substituted with cyano and/or alkyl, or -alkyl-O-aryl substitutedwith alkoxycarbonyl;

each R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl, andpharmaceutically acceptable salts, polymorphs, rotamers, prodrugs,enantiomers, hydrates, and solvates thereof, such that said subject istreated.

In yet another embodiment, the invention pertains, at least in part, tomethods for treating a subject for heart failure, congestive heartfailure, arrhythmia, diastolic dysfunction, left ventricular diastolicdysfunction, diastolic heart failure, impaired diastolic filling,systolic dysfunction, ischemia, hypertropic cardiomyopathy, suddencardiac death, myocardial and vascular fibrosis, impaired arterialcompliance, myocardial necrotic lesions, vascular damage, myocardialinfarction, left ventricular hypertrophy, decreased ejection fraction,cardiac lesions, vascular wall hypertrophy, endothelial thickening,fibrinoid necrosis of coronary arteries, renal dysfunction, liverdiseases, cerebrovascular diseases, vascular diseases, retinopathy,neuropathy, insulinopathy, edema, endothelial dysfunction, baroreceptordysfunction, migraine headaches, or hypertension, comprisingadministering to said subject an effective amount of a compound ofFormula III or IV, and pharmaceutically acceptable salts, polymorphs,rotamers, prodrugs, enantiomers, hydrates, and solvates thereof, suchthat said subject is treated.

In still another embodiment, the invention pertains, at least in part,to methods wherein the compound of the invention (e.g., a compound ofFormulae I-IV or a compound otherwise described herein) is administeredin combination with a second agent.

The term “in combination with” a second agent or treatment includesco-administration of the compound of the invention (e.g., a compound ofFormulae I-IV or a compound otherwise described herein) with the secondagent or treatment, administration of the compound of the inventionfirst, followed by the second agent or treatment and administration ofthe second agent or treatment first, followed by the compound of theinvention.

The term “second agent” includes any agent which is known in the art totreat, prevent, or reduce the symptoms of a disease or disorderdescribed herein, e.g., an aldosterone synthase associated disorder,such as, for example, hypokalemia, hypertension, Conn's disease, renalfailure, in particular, chronic renal failure, restenosis,atherosclerosis, syndrome X, obesity, nephropathy, post-myocardialinfarction, coronary heart diseases, increased formation of collagen,fibrosis and remodeling following hypertension and endothelialdysfunction, cardiovascular diseases, renal dysfunction, liver diseases,cerebrovascular diseases, vascular diseases, retinopathy, neuropathy,insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction,migraine headaches, heart failure such as congestive heart failure,arrhythmia, diastolic dysfunction, left ventricular diastolicdysfunction, diastolic heart failure, impaired diastolic filling,systolic dysfunction, ischemia, hypertropic cardiomyopathy, suddencardiac death, myocardial and vascular fibrosis, impaired arterialcompliance, myocardial necrotic lesions, vascular damage, myocardialinfarction, left ventricular hypertrophy, decreased ejection fraction,cardiac lesions, vascular wall hypertrophy, endothelial thickening, andfibrinoid necrosis of coronary arteries. Furthermore, the second agentmay be any agent of benefit to the patient when administered incombination with the administration of a compound of the invention.

Examples of second agents include HMG-Co-A reductase inhibitors,angiotensin II receptor antagonists, angiotensin converting enzyme (ACE)Inhibitors, calcium channel blockers (CCB), dual angiotensin convertingenzyme/neutral endopeptidase (ACE/NEP) inhibitors, endothelinantagonists, renin inhibitors, diuretics, ApoA-I mimics, anti-diabeticagents, obesity-reducing agents, aldosterone receptor blockers,endothelin receptor blockers, and CETP inhibitors.

The term “HMG-Co-A reductase inhibitor” (also calledbeta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitors)includes active agents that may be used to lower the lipid levelsincluding cholesterol in blood. Examples include atorvastatin,cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin,fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin,rivastatin, simvastatin, and velostatin, or, pharmaceutically acceptablesalts thereof.

The term “ACE-inhibitor” (also called angiotensin converting enzymeinhibitors) includes molecules that interrupt the enzymatic degradationof angiotensin I to angiotensin II. Such compounds may be used for theregulation of blood pressure and for the treatment of congestive heartfailure. Examples include alacepril, benazepril, benazeprilat,captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat,fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril,ramipril, spirapril, temocapril, and trandolapril, or, pharmaceuticallyacceptables salt thereof.

The term “calcium channel blocker (CCB)” includes dihydropyridines(DHPs) and non-DHPs (e.g., diltiazem-type and verapamil-type CCBs).Examples include amlodipine, felodipine, ryosidine, isradipine,lacidipine, nicardipine, nifedipine, niguldipine, niludipine,nimodipine, nisoldipine, nitrendipine, and nivaldipine, and ispreferably a non-DHP representative selected from the group consistingof flunarizine, prenylamine, diltiazem, fendiline, gallopamil,mibefradil, anipamil, tiapamil and verapamil, or, pharmaceuticallyacceptable salts thereof. CCBs may be used as anti-hypertensive,anti-angina pectoris, or anti-arrhythmic drugs.

The term “dual angiotensin converting enzyme/neutral endopetidase(ACE/NEP) inhibitor” includes omapatrilate (cf. EP 629627), fasidotrilor fasidotrilate, or pharmaceutically acceptable salts thereof.

The term “endothelin antagonist” includes bosentan (cf. EP 526708 A),tezosentan (cf. WO 96/19459), or, pharmaceutically acceptable saltsthereof.

The term “renin inhibitor” includes ditekiren (chemical name:[1S-[1R*,2R*,4R*(1R*,2R*)]]-1-[(1,1-dimethylethoxy)carbonyl]-L-prolyI-L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alfa-methyl-L-histidinamide);terlakiren (chemical name:[R—(R*,S*)]-N-(4-morpholinylcarbonyl)-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-S-methyl-L-cysteineamide);and zankiren (chemical name:[1S-[1R*[R*(R*)],2S*,3R*]]—N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-alfa-[[2-[[(4-methyl-1-piperazinyl)sulfonyl]methyl]-1-oxo-3-phenylpropyl]-amino]-4-thiazolepropanamide),or, hydrochloride salts thereof, or, SPP630, SPP635 and SPP800 asdeveloped by Speedel, or RO 66-1132 and RO 66-1168 of Formula (A) and(B):

pharmaceutically acceptable salts thereof.

The term “diuretic” includes thiazide derivatives (e.g., chlorothiazide,hydrochlorothiazide, methylclothiazide, and chlorothalidon).

The term “ApoA-I mimic” includes D4F peptides (e.g., formulaD-1N-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F)

The term “anti-diabetic agent” includes insulin secretion enhancers thatpromote the secretion of insulin from pancreatic β-cells. Examplesinclude biguanide derivatives (e.g., metformin), sulfonylureas (SU)(e.g., tolbutamide, chlorpropamide, tolazamide, acetohexamide,4-chloro-N-[(1-pyrrolidinylamino)carbonyl]-benzensulfonamide(glycopyramide), glibenclamide (glyburide), gliclazide,1-butyl-3-metanilylurea, carbutamide, glibonuride, glipizide,gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide,glymidine, glypinamide, phenbutamide, and tolylcyclamide), orpharmaceutically acceptable salts thereof. Further examples includephenylalanine derivatives (e.g., nateglinide[N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine] (cf. EP 196222and EP 526171) of the formula

repaglinide[(S)-2-ethoxy-4-{2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl}benzoicacid] (cf. EP 589874, EP 147850 A2, in particular Example 11 on page 61,and EP 207331 A1); calcium(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinlycarbonyl)-propionatedihydrate (e.g., mitiglinide (cf. EP 507534)); and glimepiride (cf. EP31058). Further examples include DPP-IV inhibitors, GLP-1 and GLP-1agonists.

DPP-IV is responsible for inactivating GLP-1. More particularly, DPP-IVgenerates a GLP-1 receptor antagonist and thereby shortens thephysiological response to GLP-1. GLP-1 is a major stimulator ofpancreatic insulin secretion and has direct beneficial effects onglucose disposal.

The DPP-IV inhibitor can be peptidic or, preferably, non-peptidic.DPP-IV inhibitors are in each case generically and specificallydisclosed e.g. in WO 98/19998, DE 196 16 486 A1, WO 00/34241 and WO95/15309, in each case in particular in the compound claims and thefinal products of the working examples, the subject-matter of the finalproducts, the pharmaceutical preparations and the claims are herebyincorporated into the present application by reference to thesepublications. Preferred are those compounds that are specificallydisclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241,respectively.

GLP-1 is an insulinotropic protein which is described, e.g., by W. E.Schmidt et al. in Diabetologia, 28, 1985, 704-707 and in U.S. Pat. No.5,705,483.

The term “GLP-1 agonists” includes variants and analogs of GLP-1(7-36)NH₂ which are disclosed in particular in U.S. Pat. No. 5,120,712,U.S. Pat. No. 5,118,666, U.S. Pat. No. 5,512,549, WO 91/11457 and by C.Orskov et al in J. Biol. Chem. 264 (1989) 12826. Further examplesinclude GLP-1(7-37), in which compound the carboxy-terminal amidefunctionality of Arg³⁶ is displaced with Gly at the 37^(th) position ofthe GLP-1 (7-36)NH₂ molecule and variants and analogs thereof includingGLN⁹-GLP-1 (7-37), D-GLN⁹-GLP-1 (7-37), acetyl LYS⁹-GLP-1 (7-37),LYS¹⁸-GLP-1 (7-37) and, in particular, GLP-1 (7-37)OH, VAL⁸-GLP-1(7-37),GLY⁸-GLP-1 (7-37), THR⁸-GLP-1 (7-37), MET⁸-GLP-1 (7-37) and4-imidazopropionyl-GLP-1. Special preference is also given to the GLPagonist analog exendin-4, described by Greig et al. in Diabetologia1999, 42, 45-50.

Also included in the definition “anti-diabetic agent” are insulinsensitivity enhancers which restore impaired insulin receptor functionto reduce insulin resistance and consequently enhance the insulinsensitivity. Examples include hypoglycemic thiazolidinedione derivatives(e.g., glitazone,(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione(englitazone),5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione(darglitazone),5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione(ciglitazone),5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(DRF2189),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione(BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637),bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-thiazolidine-2,4-dione(AD-5075),5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione(DN-108)5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione,5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione,5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(rosiglitazone),5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione(pioglitazone),5-{[4(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}-thiazolidine-2,4-dione(troglitazone),5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]-thiazolidine-2,4-dione(MCC555),5-{[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione(T-174) and5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide(KRP297)).

Further anti-diabetic agents include, insulin signalling pathwaymodulators, like inhibitors of protein tyrosine phosphatases (PTPases),antidiabetic non-small molecule mimetic compounds and inhibitors ofglutamine-fructose-6-phosphate amidotransferase (GFAT); compoundsinfluencing a dysregulated hepatic glucose production, like inhibitorsof glucose-6-phosphatase (G6Pase), inhibitors offructose-1,6-bisphosphatase (F-1,6-Bpase), inhibitors of glycogenphosphorylase (GP), glucagon receptor antagonists and inhibitors ofphosphoenolpyruvate carboxykinase (PEPCK); pyruvate dehydrogenase kinase(PDHK) inhibitors; inhibitors of gastric emptying; insulin; inhibitorsof GSK-3; retinoid X receptor (RXR) agonists; agonists of Beta-3 AR;agonists of uncoupling proteins (UCPs); non-glitazone type PPARagonists; dual PPAR

/PPARγ agonists; antidiabetic vanadium containing compounds; incretinhormones, like glucagon-like peptide-1 (GLP-1) and GLP-1 agonists;beta-cell imidazoline receptor antagonists; miglitol; α₂-adrenergicantagonists; and pharmaceutically acceptable salts thereof.

The term “obesity-reducing agent” includes lipase inhibitors (e.g.,orlistat) and appetite suppressants (e.g., sibutramine and phentermine).

The term “aldosterone receptor blocker” includes spironolactone andeplerenone.

The term “endothelin receptor blocker” includes bosentan.

The term “CETP inhibitor” refers to a compound that inhibits thecholesteryl ester transfer protein (CETP) mediated transport of variouscholesteryl esters and triglycerides from HDL to LDL and VLDL. Such CETPinhibition activity is readily determined by those skilled in the artaccording to standard assays (e.g., U.S. Pat. No. 6,140,343). Examplesinclude compounds disclosed in U.S. Pat. No. 6,140,343 and U.S. Pat. No.6,197,786 (e.g.,[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (torcetrapib); compounds disclosed in U.S. Pat. No.6,723,752 (e.g., (2R)-3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methyl]-amino}-1,1,1-trifluoro-2-propanol);compounds disclosed in U.S. patent application Ser. No. 10/807,838;polypeptide derivatives disclosed in U.S. Pat. No. 5,512,548;rosenonolactone derivatives and phosphate-containing analogs ofcholesteryl ester disclosed in J. Antibiot., 49(8): 815-816 (1996), andBioorg. Med. Chem. Lett.; 6:1951-1954 (1996), respectively. Furthermore,the CETP inhibitors also include those disclosed in WO2000/017165,WO2005/095409 and WO2005/097806.

Pharmaceutical Compositions of the Invention

The invention also pertains to pharmaceutical compositions comprising aneffective amount of a compound of Formula I:

wherein:

R^(1a), R^(2a), R^(3a), and R^(4a) are each independently hydrogen,halogen, cyano, hydroxy, alkoxy, alkyl, alkenyl, or alkoxycarbonyl;

R^(5a) is hydrogen halogen, cyano, alkyl, alkenyl, arylalkyl,heteroarylalkyl, aminocarbonyl, alkylaminocarbonyl, carboxylate,alkoxycarbonyl, heterocyclylcarbonyl, aryl, or heteroaryl;

R^(6a) and R^(7a) are each independently hydrogen, halogen, hydroxy,alkoxy, amino, alkyl, sulfonyl, —O-sulfonyl, alkylamino, heterocyclyl,aminocarbonyl, carboxylate, or alkoxycarbonyl;

R^(8a) is hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkoxycarbonyl,sulfonyl, aroyl, aryl, or heteroaryl; and pharmaceutically acceptablesalts, polymorphs, rotamers, prodrugs, enantiomers, hydrates, andsolvates thereof;

with the proviso that at least one of R^(1a)-R^(8a) is other thanhydrogen; and when R^(5a) is cyano or lower alkyl optionally substitutedwith cyano, —C(O)-piperidine, amino, alkylamino, dialkylamino,carboxylate, alkoxycarbonyl, aminocarbonyl, or heterocyclyl, then atleast one of R^(1a)-R^(4a) and R^(6a)-R^(8a) is other than hydrogen; andwhen R^(7a) is imidazolyl, then at least one of R^(1a)-R^(6a) and R^(8a)is other than hydrogen; and when R^(8a) is alkyl, arylalkyl oralkoxycarbonyl, then at least one of R^(1a)-R^(7a) is other thanhydrogen; and when R^(5a) is lower alkyl and R^(8a) is alkyl substitutedwith carboxylate or PO₃R²¹R²² wherein R²¹ and R²² are each independentlyhydrogen or lower alkyl, then at least one of R^(1a)-R^(4a) and R^(6a)and R^(7a) is other than hydrogen; and when R^(1a) is halogen and R^(5a)and R^(8a) are independently lower alkyl optionally substituted withcarboxylate, alkoxycarbonyl, or —C(O)-piperidine, then at least one ofR^(1a), R^(2a), R^(4a), R^(5a), and R^(7a) is other than hydrogen; andwhen R^(3a) is halogen or lower alkyl and R^(5a) is lower alkylsubstituted with dialkylamino, dialkylaminocarbonyl, carboxylate,alkoxycarbonyl or aminocarbonyl, then at least one of R^(1a), R^(2a),R^(5a) and R^(6a)-R^(8a) is other than hydrogen; and when R^(2a) andR^(1a) are each alkoxy and R^(5a) is cyano, then at least one of R^(1a),R^(4a), and R^(6a)-R^(8a) is other than hydrogen; and when R^(1a) isalkyl substituted with aroyl, and R⁵ and R⁸ are each independentlyhydrogen or lower alkyl, then at least one of R^(1a), R^(2a), and R^(4a)is other than hydrogen, wherein said effective amount is effective totreat an aldosterone synthase associated state.

In another embodiment, the invention pertains to pharmaceuticalcompositions comprising an effective amount of a compound of Formula II:

wherein:

R^(2q) is hydrogen or halogen;

R^(3q) is hydrogen, halogen, or cyano;

R^(5q) is hydrogen, alkyl, or cyano;

R^(7q) hydrogen, halogen, alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl,—NR′—SO₂-alkyl, —NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl, —NR′—C(O)—O-alkyl,haloalkyl, or alkyl optionally substituted with heterocyclyl,—NR′—SO₂-alkyl, —NR′—SO₂-haloalkyl, NR′—C(O)-alkyl,NR′—C(O)-heterocyclyl, —NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl;

R^(8q) is hydrogen, alkyl, hydroxyalkyl, -alkyl-OC(O)-alkyl,carboxylate, alkoxycarbonyl, or arylalkyl substituted with alkyl, oraroyl substituted with cyano and/or alkyl, or -alkyl-O-aryl substitutedwith alkoxycarbonyl;

each R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl,

with the proviso that at least one of R^(2q), R^(3q), R^(5q), R^(7q) andR^(8q) is other than hydrogen, wherein said effective amount iseffective to treat an aldosterone synthase associated state.

In still another embodiment, the invention pertains to pharmaceuticalcompositions comprising an effective amount of a compound of Formula IIIor IV, wherein said effective amount is effective to treat analdosterone synthase associated state.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredients for asubject of about 50-70 kg, preferably about 1-500 mg or about 1-250 mgor about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of activeingredients. The therapeutically effective dosage of a compound, thepharmaceutical composition, or the combinations thereof, is dependent onthe species of the subject, the body weight, age and individualcondition, the disorder or disease or the severity thereof beingtreated. A physician, clinician or veterinarian of ordinary skill canreadily determine the effective amount of each of the active ingredientsnecessary to prevent, treat or inhibit the progress of the disorder ordisease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., preferably aqueous solutions, and in vivo either enterally,parenterally, advantageously intravenously, e.g., as a suspension or inaqueous solution. The dosage in vitro may range between about 10⁻³ molarand about 10⁻⁹ molar concentrations, or between about 10⁻⁶ molar andabout 10⁻⁹ molar concentrations.

The activities of a compound according to the present invention can beassessed by both in vitro and in vivo methods.

The term “pharmaceutically acceptable carrier” includes any and allsolvents, dispersion media, coatings, surfactants, antioxidants,preservatives (e.g., antibacterial agents, antifungal agents), isotonicagents, absorption delaying agents, salts, preservatives, drugs, drugstabilizers, binders, excipients, wetting agents, emulsifiers, buffers,disintegration agents, lubricants, coatings, sweetening agents,flavoring agents, dyes, such like materials and combinations thereof, aswould be known to one of ordinary skill in the art (see, for example,Remington's Pharmaceutical Sciences, 18^(th) Ed. Mack Printing Company,1990, pp. 1289-1329, incorporated herein by reference). Except insofaras any conventional carrier is incompatible with the active ingredient,its use in the therapeutic or pharmaceutical compositions iscontemplated. Suitable pharmaceutically acceptable carriers include butare not limited to water, salt solutions, alcohol, vegetable oils,polyethylene glycols, gelatin, lactose, amylase, magnesium stearate,talc, silicic aid, viscous paraffin, perfume oil, fatty acidmonoglycerides and diglycerides, petroethral fatty acid esters,hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.

The pharmaceutical compositions of the invention can be formulated forparticular routes of administration such as oral administration,parenteral administration, and rectal administration, etc. In addition,the pharmaceutical compositions of the present invention can be made upin a solid form including capsules, tablets, pills, granules, powders orsuppositories, or in a liquid form including solutions, suspensions oremulsions. The pharmaceutical compositions can be subjected toconventional pharmaceutical operations such as sterilization and/or cancontain conventional inert diluents, lubricating agents, or bufferingagents, as well as adjuvants, such as preservatives, stabilizers,wetting agents, emulsifers and buffers, etc.

In certain embodiments, the pharmaceutical compositions are tablets andgelatin capsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, ag, starches, agar, alginic acid or its sodium        salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withnontoxic pharmaceutically acceptable excipients which are suitable forthe manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure, and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, preferably about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with carrier. Advantageouscarriers include absorbable pharmacologically acceptable solvents toassist passage through the skin of the host. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound of the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays, etc. They are thusparticularly suited for use in topical, including cosmetic, formulationswell-known in the art. Such may contain solubilizers, stabilizers,tonicity enhancing agents, buffers and preservatives.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

One embodiment of the invention includes a pharmaceutical composition asdescribed above in combination with a second agent and a pharmaceuticalcarrier.

In yet another embodiment, the invention pertains, at least in part, tocompounds of Formula I:

wherein:

R^(1a), R^(2a), R^(3a), and R^(4a) are each independently hydrogen,halogen, cyano, hydroxy, alkoxy, alkyl, alkenyl, or alkoxycarbonyl;

R^(5a) is hydrogen halogen, cyano, alkyl, alkenyl, arylalkyl,heteroarylalkyl, aminocarbonyl, alkylaminocarbonyl, carboxylate,alkoxycarbonyl, heterocyclylcarbonyl, aryl, or heteroaryl;

R^(6a) and R^(7a) are each independently hydrogen, halogen, hydroxy,alkoxy, amino, alkyl, sulfonyl, —O-sulfonyl, alkylamino, heterocyclyl,aminocarbonyl, carboxylate, or alkoxycarbonyl;

R^(8a) is hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkoxycarbonyl,sulfonyl, aroyl, aryl, or heteroaryl; and pharmaceutically acceptablesalts, polymorphs, rotamers, prodrugs, enantiomers, hydrates, andsolvates thereof;

with the proviso that at least one of R^(1a)-R^(8a) is other thanhydrogen; and when R^(5a) is cyano or lower alkyl optionally substitutedwith cyano, —C(O)-piperidine, amino, alkylamino, dialkylamino,carboxylate, alkoxycarbonyl, aminocarbonyl, or heterocyclyl, then atleast one of R^(1a)-R^(4a) and R^(6a)-R^(8a) is other than hydrogen; andwhen R^(7a) is imidazolyl, then at least one of R^(1a)-R^(6a) and R^(8a)is other than hydrogen; and when R^(8a) is alkyl, arylalkyl oralkoxycarbonyl, then at least one of R^(1a)-R^(7a) is other thanhydrogen; and when R^(5a) is lower alkyl and R^(2a) is alkyl substitutedwith carboxylate or PO₃R²¹R²² wherein R²¹ and R²² are each independentlyhydrogen or lower alkyl, then at least one of R^(1a)-R^(4a) and R^(8a)and R^(7a) is other than hydrogen; and when R^(1a) is halogen and R^(5a)and R^(8a) are independently lower alkyl optionally substituted withcarboxylate, alkoxycarbonyl, or —C(O)-piperidine, then at least one ofR^(1a), R^(2a), R^(4a), R^(5a), and R^(a) is other than hydrogen; andwhen R^(3a) is halogen or lower alkyl and R^(5a) is lower alkylsubstituted with dialkylamino, dialkylaminocarbonyl, carboxylate,alkoxycarbonyl or aminocarbonyl, then at least one of R^(1a), R^(2a),R^(4a) and R^(6a)-R^(8a) is other than hydrogen; and when R^(2a) andR^(3a) are each alkoxy and R^(5a) is cyano, then at least one of R^(1a),R^(4a), and R^(8a)-R^(2a) is other than hydrogen; and when R^(1a) isalkyl substituted with aroyl, and R⁵ and R⁸ are each independentlyhydrogen or lower alkyl, then at least one of R^(1a), R^(2a), and R^(4a)is other than hydrogen, for use in therapy.

In still another embodiment, the invention pertains, at least in part,to compounds of Formula II:

wherein:

R^(2q) is hydrogen or halogen;

R^(3q) is hydrogen, halogen, or cyano;

R^(5q) is hydrogen, alkyl, or cyano;

R^(7q) is hydrogen, halogen, alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl,—NR′—SO₂-alkyl, —NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl, —NR′—C(O)—O-alkyl,haloalkyl, or alkyl optionally substituted with heterocyclyl,—NR′—SO₂-alkyl, —NR′—SO₂-haloalkyl, NR′—C(O)-alkyl,NR′—C(O)-heterocyclyl, —NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl;

R^(8q) is hydrogen, alkyl, hydroxyalkyl, -alkyl-OC(O)-alkyl,carboxylate, alkoxycarbonyl, or arylalkyl substituted with alkyl, oraroyl substituted with cyano and/or alkyl, or -alkyl-O-aryl substitutedwith alkoxycarbonyl;

each R′ is independently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl,

-   -   with the proviso that at least one of R^(2q), R^(3q), R^(5q),        R^(7q) and R^(8q) is other than hydrogen, for use in therapy.

Another embodiment of the invention pertains, at least in part, tocompounds of Formula III or IV, for use in therapy.

Still another embodiment of the invention pertains, at least in part, tothe use of compounds of Formula (I), (II), (III) or (IV), as describedabove, and the compounds of the examples, for the preparation of apharmaceutical composition for the treatment of a disorder or disease ina subject mediated by the inhibition of aldosterone synthase.

In yet another embodiment, the invention pertains, at least in part, tocompounds of Formula (I), (II), (III) or (IV), as described above, andthe compounds of the examples, for use as a medicament.

Another embodiment of the invention pertains, at least in part, topharmaceutical compositions, as described above, for use as amedicament.

In another embodiment, the invention pertains, at least in part, to theuse of pharmaceutical compositions, as described above, for thepreparation of a medicament for the treatment of a disorder or diseasein a subject mediated by the inhibition of aldosterone synthase.

Another embodiment of the invention pertains, at least in part, tomethods of treating a disorder or disease mediated by aldosteronesynthase in a mammal, by administering to the mammal in need thereof atherapeutically effective amount of a compound of Formula (I), (II),(III) or (IV), as described above and in the examples.

Another embodiment of the invention pertains to kits comprising, apharmaceutical composition as described above, packaged withinstructions for use of the pharmaceutical composition in the treatmentof an aldosterone synthase associated state in a subject in needthereof.

EXEMPLIFICATION OF THE INVENTION

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

Example 1 3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride

3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride is synthesized based onthe method described in U.S. Pat. No. 3,468,894. A flask is charged with3-propionylpyridine (1.004 g, 7.279 mmol), phenylhydrazine hydrochloride(1.010 g, 6.915 mmol) and ethanol (15 mL). The mixture is heated toreflux for 1 h and cooled to room temperature. To a portion of thereaction mixture (2.5 mL) is added HCl (4M in dioxane, 1 mL, 4 mmol) andthe mixture is heated to reflux. After 3 h, the mixture is concentratedin vacuo. The solid is dissolved in the minimum amount of boilingmethanol (17 mL) and allowed to cool slowly to room temperature. A solidprecipitates and after cooling to 0° C. for 30 min, the yellow solid isfiltered off, washed with portions of cold methanol and dried under highvacuum to give 3-methyl-2-pyridin-3-yl-1H-indole hydrochloride as yellowneedles. ¹H NMR (400 MHz, MeOD) δ ppm (HCl salt) 2.56 (s, 3H), 7.09-7.13(m, 1H), 7.23-7.26 (m, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.63 (d, J=8.1 Hz,1H), 8.14-8.18 (m, 1H), 8.74 (d, J=5.8 Hz, 1H), 8.83-8.85 (m, 1H), 9.08(s, 1H).

Example 2 5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride

5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride is synthesizedbased on the method described in U.S. Pat. No. 3,468,894.(4-Chloro-phenyl)-hydrazine hydrochloride (3.0 g, 16.8 mmol) and3-propionylpyridine (2.4 g, 17.6 mmol) in ethanol (45 mL) is heated toreflux for 6 h. The mixture is then cooled to room temperature and addedto HCl (4M in 1,4-dioxane, 17.6 mL). The resulting mixture is heated toreflux for 24 h. The mixture is then cooled to room temperature and theyellow precipitate is filtered and washed with methanol (10 mL) threetimes to give 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochlorideas a yellow solid. MS (ESI) m/z 243.0 and 244.9 (M+H)⁺.

Example 3 5-Fluoro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride

(4-Fluoro-phenyl)-hydrazine hydrochloride is processed according to theprocedure described in Example 2 to give5-fluoro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride. MS (ESI) m/z227.0 (M+H)⁺.

Example 4 4- and 6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride

(3-Fluoro-phenyl)-hydrazine hydrochloride is processed according to theprocedure described in Example 2 to give a mixture of4-fluoro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride and6-fluoro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride. MS (ESI) m/z227.0 (M+H)⁺.

Example 5 4- and 6-Chloro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride

(3-Chloro-phenyl)-hydrazine hydrochloride is processed according to theprocedure described in Example 2 to give a mixture of4-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride and6-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride. MS (ESI) m/z242.96 and 244.98 (M+H)⁺.

Example 6 (a) 5-Bromo-3-methyl-2-pyridin-3-yl-1H-indole

To a suspension of 4-bromophenylhydrazine hydrochloride (10.00 g, 42.95mmol) in anhydrous ethanol (200 mL) is added 3-propionylpyridine (7.51g, 42.95 mmol) and the mixture is stirred at reflux for 30 min. 4M HClin 1,4-dioxane (42.9 mL) is added to the yellow solution and stirring iscontinued at reflux overnight. The reaction mixture is cooled with anice-water bath and the yellow precipitate is filtered through a sinteredfunnel to give 5-bromo-3-methyl-2-pyridin-3-yl-1H-indole hydrochlorideas a yellow solid. The product is dissolved in methanol (100 mL) andtreated with sodium methoxide to give the free base, which is used inthe next step without further purification.

(b) 3-Methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile

5-Bromo-3-methyl-2-pyridin-3-yl-1H-indole (5.0 g, 16.7 mmol) and copper(I) cyanide (1.9 g, 20.1 mmol) are placed in a round bottom flask whichis flushed with N₂. N-Methylpyrrolidinone (40 mL) is added via syringe.The resulting mixture is heated to 200° C. under N₂ with vigorousstirring overnight. The mixture is cooled to room temperature anddichloromethane (200 mL) is added. The mixture is filtered through a padof celite. The filtrate is washed with 10% aqueous ammonia in saturatedaqueous ammonium chloride. The aqueous phase is extracted withdichloromethane. The combined organic phase is dried over sodium sulfateand concentrated. The residue is purified by silica gel flashchromatography (ethyl acetate-heptane, 0:1 to 1:0) to give3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.45 (s, 3H), 7.45-7.60 (m, 3H), 8.06-8.11 (m, 1H), 8.15(s, 1H), 8.60 (dd, J=4.8, 1.5 Hz, 1H), 8.91 (d, J=1.5 Hz, 1H), 11.94(br. s., 1H). HRMS (ESI) m/z 234.1031 [(M+H)⁺Calcd for C₁₅H₁₁N₃,234.1031].

Example 7 (a)N-(4-Fluoro-phenyl)-N′-[1-pyridin-3-yl-eth-(Z)-ylidene]-hydrazine

3-Acetylpyridine (5.00 g, 40.45 mmol) and 4-fluorophenylhydrazinehydrochloride (6.44 g, 38.43 mmol) are suspended in ethanol (70 mL) andheated to reflux. After 1 h, HCl (4M in dioxane, 150 mL, 600 mmol) isadded and the mixture is heated to reflux for 16 h. The mixture isconcentrated in vacuo and taken up in a little ethanol. The solid isfiltered off and washed with ethanol to give a yellow solid. Thefiltrate is concentrated to dryness. The resulting solid is washed withsmall amounts of ice-cold ethanol and filtered off. The two fractionsare combined and used in the next step without further purification.

(b) 5-Fluoro-2-pyridin-3-yl-indole

A flask is charged with polyphosphoric acid (1.2 g) andN-(4-fluoro-phenyl)-N′-[1-pyridin-3-yl-eth-(Z)-ylidene]-hydrazine (1.0g) is added. The mixture is stirred with a thermometer and heated to160° C. (internal temperature), whereupon the paste is allowed to coolto 100° C. Water (90 mL) and ethyl acetate are added and the mixture isvigorously stirred until a discrete yellow precipitate is obtained. Theprecipitate is filtered off and the two phases are separated. The ethylacetate phase is discarded. The solids and aqueous phase are combinedand 1M aqueous NaOH is added, followed with chloroform, and the mixtureis vigorously stirred until full dissolution. The aqueous phase isextracted with chloroform and the combined organic phase is dried overMgSO₄ and concentrated in vacuo. The residue is purified by silica gelflash chromatography (ethyl acetate-heptane, 7:3 to 9:1) to give as abrown solid. MS (ESI) m/z 213 (M+H)⁺.

Example 8 (a)N-(4-Bromo-phenyl)-N′-[1-pyridin-3-yl-eth-(Z)-ylidene]-hydrazinehydrochloride

To a solution of 4-bromophenylhydrazine hydrochloride (11.5 g, 50 mmol)in anhydrous ethanol (200 mL) is added 3-acetylpyridine (6.1 g, 50mmol). The mixture is heated to 90° C. and stirred for 3 h, cooled toroom temperature and filtered through a sintered glass funnel. The solidis washed with ethanol and placed under high vacuum overnight to giveN-(4-bromo-phenyl)-N′-[1-pyridin-3-yl-eth-(Z)-ylidene]-hydrazinehydrochloride as a yellow solid.

(b) 2-Pyridin-3-yl-1H-indole-5-carbonitrile

A flask fitted with a mechanical stirrer is charged with polyphosphoricacid (15 g) andN-(4-bromo-phenyl)-N′-[1-pyridin-3-yl-eth-(Z)-ylidene]-hydrazinehydrochloride (18 g) is heated to 210° C. (oil bath temperature) for 1h. The paste is allowed to cool to ambient temperature and 1M aqueousNaOH is added, followed with chloroform, and the mixture is vigorouslystirred until full dissolution. The aqueous phase is extracted withchloroform and the combined organic phase is dried over MgSO₄ andconcentrated in vacuo to give 5-bromo-2-pyridin-3-yl-1H-indole as abrown solid which is used without further purification.

5-Bromo-2-pyridin-3-yl-1H-indole (7.0 g, 21.8 mmol) and copper (I)cyanide (2.3 g, 26.1 mmol) are placed in a round bottom flask which isflushed with N₂. N-Methylpyrrolidinone (40 mL) is added via syringe. Theresulting mixture is heated to 160° C. under N₂ with vigorous stirringovernight. The mixture is cooled to room temperature and poured into 10%aqueous ammonia in saturated aqueous ammonium chloride (300 mL). Theaqueous phase is extracted with dichloromethane (100 mL) five times. Thecombined organic phase is dried over sodium sulfate and concentrated.The residue is purified by silica gel flash chromatography (ethylacetate-heptane, 0:1 to 1:0) to give2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.20 (s, 1H), 7.48 (dd, J=8.3, 1.5 Hz, 1H), 7.51-7.55 (m, 1H), 7.59 (d,J=8.6 Hz, 1H), 8.12 (s, 1H), 8.25-8.29 (m, 1H), 8.56 (dd, J=4.8, 1.5 Hz,1H), 9.14 (d, J=1.8 Hz, 1H), 12.27 (s, 1H). HRMS (ESI) m/z 220.0869[(M+H)⁺Calcd for C₁₄H₉N₃, 220.0875].

Example 9 1-Benzyl-3-methyl-2-pyridin-3-yl-1H-indole

3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1, 0.110 g,0.445 mmol) is suspended in THF (3 mL) and cooled to 0° C. KHMDS (0.5Min toluene, 2 mL, 1 mmol) is added dropwise, the cooling bath is loweredand the mixture is stirred at room temperature for 15 min, whereupon itis lowered in the ice-water bath. Benzyl bromide (0.093 g, 0.534 mmol)is added dropwise. After 3 h, additional benzyl bromide (0.046 g, 0.267mmol) is added, and upon reaction completion, the mixture is quenchedwith 1M aqueous HCl and diluted with ethyl acetate. The aqueous phase isextracted and the combined organic phase is dried over MgSO₄, filteredand concentrated in vacuo. Purification of the residue by silica gelflash chromatography (dichloromethane-methanol, 99:1) affords1-benzyl-3-methyl-2-pyridin-3-yl-1H-indole as a pale yellow solid. ¹HNMR (400 MHz, MeOD) δ ppm 2.18 (s, 3H), 5.19 (s, 2H), 6.69-6.71 (m, 2H),7.01-7.11 (m, 5H), 7.21 (d, J=8.1 Hz, 1H), 7.37-7.41 (m, 1H), 7.52 (d,J=7.8 Hz, 1H), 7.67-7.70 (m, 1H), 8.36 (s, 1H), 8.43-8.45 (m, 1H). MS(ESI) m/z 299 (M+H)⁺.

Example 103-Methyl-1-(5-methyl-isoxazol-3-ylmethyl)-2-pyridin-3-yl-1H-indolehydrochloride

A flask is charged with 3-methyl-2-pyridin-3-yl-1H-indole hydrochloride(Example 1, 0.100 g, 0.408 mmol) in THF (2.5 mL) and cooled to 0° C.KHMDS (0.5 M in toluene, 1.8 mL, 0.898 mmol) is added and the mixture isstirred at room temperature for 30 min, followed by addition of3-bromomethyl-5-methyl-isoxazole (0.144 g, 0.817 mmol). The reactionmixture is stirred for 0.5 h, then quenched with saturated ammoniumchloride solution and extracted with ethyl acetate. The organic layer isdried over sodium sulfate and concentrated in vacuo. The residue ispurified by reverse phase H PLC with Xbridge Shield RP18 column and a0.1% aqueous NH₄OH in acetonitrile gradient to afford3-methyl-1-(5-methyl-isoxazol-3-ylmethyl)-2-pyridin-3-yl-1H-indoleproduct as a colorless oil. The oil is dissolved in diethyl ether andfew drops of concentrated HCl are added. The volatiles are removed invacuo and the reside is lyophilized to afford the product as a yellowsolid. ¹H NMR (400 MHz, MeOD) δ ppm (HCl salt) 2.30 (s, 3H), 2.31 (s,3H), 5.30 (s, 2H), 5.67 (s, 1H), 7.18 (t, J=8.0 Hz, 1H), 7.27 (ddd,J=7.6, 1.1 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.56-7.69 (m, 2H), 7.99 (dt,J=8.0, 1.9, 1.8 Hz, 1H), 8.56-8.68 (m, 2H). HRMS (ESI) m/z 304.1440[(M+H)⁺Calcd for C₁₉H₁₈N₃O, 304.1450].

Example 114-(5-Chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester

To a solution of 5-chloro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride (Example 2, 558 mg, 2.0 mmol) in THF (20 mL) is added 0.5M KHMDS in toluene (8.8 mL, 4.4 mmol) and the mixture is stirred at roomtemperature for 30 min, whereupon 4-bromomethyl-benzoic acid methylester (916 mg, 4.0 mmol). The reaction mixture is stirred for 3 h.Methanol is added to quench the reaction and the solvents are removed invacuo. The residue is purified by flash chromatography with 1-3%methanol in dichloromethane to give4-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester. MS (ESI) m/z 391.3 and 393.3 (M+H)⁺.

Example 124-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester

The mixture of 4- and 6-fluoro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride (Example 4) and 4-bromomethyl-benzoic acid methyl esterare processed according to the method described in Example 11.Separation of the regioisomers is done on an X-Bridge RP18 eluting witha 30-70% gradient of acetonitrile in 0.1% NH₄OH to give4-(6-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.30 (s, 3H), 3.90 (s, 3H),5.22 (s, 2H), 6.86 (dd, J=9.8, 2.1 Hz, 1H), 6.93-7.00 (m, 3H), 7.34-7.38(m, 1H), 7.55-7.61 (m, 2H), 7.90-7.92 (m, 1H), 7.92-7.94 (m, 1H), 8.59(dd, J=2.3, 0.9 Hz, 1H), 8.63 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z375.1498 [(M+H)⁺Calcd for C₂₃H₂₀FN₂O₂, 375.1509].

Example 134-(4-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester

The method described in Example 12 also yields4-(4-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester. MS (ESI) m/z 375.2 (M+H)⁺.

Example 143-(5-Chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile

5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2) and3-bromomethyl-benzonitrile are processed according to the methoddescribed in Example 11 to give3-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile.¹H NMR (400 MHz, MeOD) δ ppm 2.25 (s, 3H), 5.36 (s, 2H), 7.03 (d, J=7.8Hz, 1H), 7.14 (s, 1H), 7.18 (dd, J=8.6, 2.0 Hz, 1H), 7.33 (d, J=8.6 Hz,1H), 7.36 (t, J=7.7 Hz, 1H), 7.49-7.56 (m, 2H), 7.62 (d, J=2.0 Hz, 1H),7.81 (dt, J=7.8, 1.9 Hz, 1H), 8.47 (d, J=2.3 Hz, 1H), 8.58 (dd, J=5.1,1.8 Hz, 1H). HRMS (ESI) m/z 358.1102 [(M+H)⁺Calcd for C₂₂H₁₇ClN₃,358.1111].

Example 153-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrilehydrochloride

The mixture of 4- and 6-fluoro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride (Example 4) and 3-bromomethyl-benzonitrile are processedaccording to the method described in Example 11. Separation of theregioisomers is done on a Chiralcel® OD eluting with heptane-isopropanol4:1 to give3-(6-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm (HCl salt) 2.23 (s, 3H), 5.41 (s, 2H),6.96-7.06 (m, 2H), 7.27 (s, 1H), 7.37-7.43 (m, 2H), 7.62-7.69 (m, 2H),7.81 (t, J=6.3 Hz, 1H), 8.17 (d, J=7.3 Hz, 1H), 8.75-8.82 (m, 2H). HRMS(ESI) m/z 342.1405 [(M+H)⁺Calcd for C₂₂H₁₇FN₃: 342.1407]

Example 163-(4-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrilehydrochloride

The mixture of 4- and 6-fluoro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride (Example 4) and 3-bromomethyl-benzonitrile are processedaccording to the method described in Example 11. Separation of theregioisomers is done on a Chiralcel® OD eluting with heptane-isopropanol4:1 to give3-(4-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm (HCl salt) 2.33 (s, 3H), 5.41 (s, 2H),6.87 (dd, J=11.4, 7.8 Hz, 1H), 7.06 (d, J=7.1 Hz, 1H), 7.12-7.21 (m,1H), 7.26-7.34 (m, 2H), 7.42 (t, J=7.7 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H),7.81 (dd, J=7.2, 5.2 Hz, 1H), 8.18 (d, J=7.3 Hz, 1H), 8.79 (br. s., 2H).HRMS (ESI) m/z 342.1407 [(M+H)⁺Calcd for C₂₂H₁₇FN₃: 342.1407].

Example 174-(5-Chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile

5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2) and4-bromomethyl-benzonitrile are processed according to the methoddescribed in Example 11 to give4-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile.¹H NMR (400 MHz, MeOD) δ ppm 2.28 (s, 3H), 5.42 (s, 2H), 6.98 (d, J=8.3Hz, 1H), 7.20 (dd, J=8.6, 2.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.55 (dd,J=7.8, 5.1 Hz, 1H), 7.57-7.62 (m, 2H), 7.66 (d, J=2.0 Hz, 1H), 7.84 (dt,J=7.8, 1.9 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.60 (dd, J=4.9, 1.6 Hz,1H). HRMS (ESI) m/z 358.1120 [(M+H)⁺Calcd for C₂₂H₁₇ClN₃: 358.1111].

Example 184-(4-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrilehydrochloride

The mixture of 4- and 6-fluoro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride (Example 4) and 4-bromomethyl-benzonitrile are processedaccording to the method described in Example 11. Separation of theregioisomers is done on a Chiralcel® OD eluting with heptane-isopropanol4:1 to give4-(4-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm (HCl salt) 2.34 (s, 3H), 5.46 (s, 2H),6.87 (dd, J=11.4, 7.8 Hz, 1H), 6.96 (d, J=8.6 Hz, 2H), 7.11-7.20 (m,1H), 7.29 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.3 Hz, 2H), 7.72-7.80 (m, 1H),8.05-8.14 (m, 1H), 8.71-8.79 (m, 2H). HRMS (ESI) m/z 342.1407[(M+H)⁺Calcd for C₂₂H₁₇FN₃: 342.1407].

Example 194-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile

The mixture of 4- and 6-fluoro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride (Example 4) and 4-bromomethyl-benzonitrile are processedaccording to the method described in Example 11. Separation of theregioisomers is done on a Chiralcel® OD eluting with heptane-isopropanol4:1 to give4-(6-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile.¹H NMR (400 MHz, CDCl₃) δ ppm 2.30 (s, 3H), 5.22 (s, 2H), 6.83 (dd,J=9.7, 2.1 Hz, 1H), 6.93-7.01 (m, 3H), 7.36 (dd, J=7.6, 5.1 Hz, 1H),7.49-7.63 (m, 4H), 8.56 (d, J=1.3 Hz, 1H), 8.64 (d, J=3.5 Hz, 1H). HRMS(ESI) m/z 342.1390 [(M+H)⁺ Calcd for C₂₂H₁₇FN₃: 342.1407].

Example 201-(4-Methanesulfonyl-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole

3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1) and1-bromomethyl-4-methanesulfonyl-benzene are processed according to themethod described in Example 11 to give1-(4-methanesulfonyl-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole. ¹H NMR(400 MHz, MeOD) δ ppm 2.33 (s, 3H), 3.08 (s, 3H), 5.46 (s, 2H), 7.08 (d,J=8.1 Hz, 2H), 7.18 (t, J=7.3 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.34 (d,J=8.1 Hz, 1H), 7.55 (dd, J=7.8, 4.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H),7.81 (d, J=8.3 Hz, 2H), 7.85 (dt, J=7.8, 1.9 Hz, 1H), 8.52 (d, J=2.3 Hz,1H), 8.59 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 377.1318 [(M+H)⁺Calcdfor C₂₂H₂₁N₂O₂S: 377.1324].

Example 215-Chloro-1-(4-methanesulfonyl-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole

5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2) and1-bromomethyl-4-methanesulfonyl-benzene are processed according to themethod described in Example 11 to give5-chloro-1-(4-methanesulfonyl-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole.¹H NMR (400 MHz, MeOD) δ ppm 2.29 (s, 3H), 3.09 (s, 3H), 5.46 (s, 2H),7.20 (dd, J=8.6, 2.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.53-7.57 (m, 1H),7.66 (d, J=1.8 Hz, 1H), 7.79-7.84 (m, 1H), 7.86 (dt, J=7.9, 2.0 Hz, 1H),8.52 (dd, J=2.3, 1.0 Hz, 1H), 8.61 (dd, J=5.1, 1.8 Hz, 1H). HRMS (ESI)m/z 411.0927 [(M+H)⁺ Calcd for C₂₂H₂₀N₂O₂SCl: 411.0934].

Example 22 1-(3-Benzyloxy-benzyl)-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride

3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1) and1-benzyloxy-4-bromomethyl-benzene are processed according to the methoddescribed in Example 11 to give1-(3-benzyloxy-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole. ¹H NMR (400MHz, MeOD) δ ppm (HCl salt) 2.31 (s, 3H), 4.91 (s, 2H), 5.28 (s, 2H),6.37 (s, 1H), 6.45 (d, J=7.6 Hz, 1H), 6.82 (dd, J=8.2, 2.1 Hz, 1H), 7.12(t, J=7.8 Hz, 1H), 7.16-7.22 (m, 1H), 7.22-7.38 (m, 7H), 7.61 (dd,J=8.0, 5.2 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.85 (dt, J=8.0, 1.8 Hz,1H), 8.46 (d, J=1.3 Hz, 1H), 8.60 (dd, J=5.1, 1.5 Hz, 1H). HRMS (ESI)m/z 405.1969 [(M+H)⁺Calcd for C₂₈H₂₅N₂O: 405.1967].

Example 23 (a) 5-Formyl-2-methylsulfanyl-benzonitrile

A flask is charged with 5-fluoro-2-formyl-benzonitrile (0.200 g, 1.34mmol), potassium carbonate (0.371 g, 0.268 mmol), sodium thiomethoxide(0.142 g, 2.01 mmol) and DMF (20 mL). The mixture is stirred at roomtemperature for 10 min, then diluted with ethyl acetate and washed withwater. The organic layer is dried over sodium sulfate and concentratedin vacuo to afford 5-formyl-2-methylsulfanyl-benzonitrile as a yellowcolor solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.64 (s, 3H), 7.41 (d, J=8.3Hz, 1H), 8.01 (dd, J=8.5, 1.9 Hz, 1H), 8.07 (d, J=1.8 Hz, 1H), 9.95 (s,1H).

(b) 5-Hydroxymethyl-2-methylsulfanyl-benzonitrile

A flask is charged with 5-formyl-2-methylsulfanyl-benzonitrile (1.0 g,5.68 mmol) in MeOH (20 mL) and cooled to 0° C. Sodium borohydride (1.07g, 28.40 mmol) is added and the mixture is stirred at room temperaturefor 2 h, followed by removal of solvent in vacuo. The residue isre-dissolved in dichloromethane and washed with water twice. The organiclayer is dried over sodium sulfate and concentrated in vacuo to afford5-hydroxymethyl-2-methylsulfanyl-benzonitrile as a white solid. ¹H NMR(400 MHz, CDCl₃) δ ppm 2.57 (s, 3H), 4.70 (d, J=5.1 Hz, 2H), 7.33 (d,J=8.3 Hz, 1H), 7.53 (dd, J=8.3, 1.0 Hz, 1H), 7.62 (s, 1H).

(c) 5-Hydroxymethyl-2-methanesulfonyl-benzonitrile

A flask is charged with 5-hydroxymethyl-2-methylsulfanyl-benzonitrile(0.866 g, 4.86 mmol) in a mixture of MeOH (10 mL) and water (10 mL).Oxone (7.47 g, 12.16 mmol) is added and the mixture is stirred at roomtemperature for 16 h. The residue is acidified to pH 1 using aqueous 1MHCl and then extracted with dichloromethane twice. The organic layer isdried over sodium sulfate and concentrated in vacuo to afford5-hydroxymethyl-2-methanesulfonyl-benzonitrile as a white solid. ¹H NMR(400 MHz, CDCl₃) δ ppm 3.28 (s, 3H), 4.89 (s, 2H), 7.80 (d, J=8.1 Hz,1H), 7.95 (s, 1H), 8.18 (d, J=8.1 Hz, 1H).

(d) 5-Bromomethyl-2-methanesulfonyl-benzonitrile

A flask is charged with 5-hydroxymethyl-2-methylsulfonyl-benzonitrile(0.788 g, 3.73 mmol) in toluene (5 mL) and heated at 40° C. PBr₃ (0.175mL, 1.86 mmol) is added and the reaction is refluxed for 0.5 h. It isthen cooled to room temperature, diluted with dichloromethane and washedwith water. The aqueous layer is extracted with dichloromethane. Thecombined organic layer is dried over sodium sulfate and concentrated invacuo to afford 5-bromomethyl-2-methanesulfonyl-benzonitrile as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.28 (s, 3H), 4.89 (s, 2H), 7.80(d, J=8.3 Hz, 1H), 7.94 (s, 1H), 8.18 (d, J=8.1 Hz, 1H).

(e)2-Methanesulfonyl-5-(3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzonitrile

The product in Example 1 is processed according to the method describedin Example 11 to give2-methanesulfonyl-5-(3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzonitrile.¹H NMR (400 MHz, MeOD) δ ppm 2.35 (s, 3H), 3.27 (s, 3H), 5.53 (s, 2H),7.19-7.31 (m, 3H), 7.37 (d, J=8.1 Hz, 1H), 7.51 (d, J=1.3 Hz, 1H), 7.65(dd, J=7.8, 5.1 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H),8.02 (d, J=8.1 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.65 (dd, J=5.1, 1.5 Hz,1H). HRMS (ESI) m/z 402.1269 [(M+H)⁺Calcd for C₂₃H₂₃N₃O₂S: 402.1276].

Example 24 (a) N-methyl-N-methoxy-nicotinamide

A flask is charged with nicotinic acid (5.0 g, 40.6 mmol). Thionylchloride (30.0 mL) is added and the reaction is refluxed for 1 h. It isthen cooled to room temperature and concentrated in vacuo. The residueis dissolved in anhydrous dichloromethane (30 mL) andO,N-dimethyl-hydroxylamine (4.35 g, 44.0 mmol) is added, followed byaddition of triethylamine (14.15 g, 100.0 mmol). The reaction mixture isstirred at room temperature for 1.5 h. It is then washed with water andthe aqueous phase is extracted with dichloromethane. The combinedorganic layer is dried over sodium sulfate and concentrated in vacuo toafford N-methyl-N-methoxy-nicotinamide as a brown oil. MS (ESI) m/z167.0 (M+H)⁺.

(b) 1-Pyridin-3-yl-butan-1-one

A flask is charged with N-methyl-N-methoxy-nicotinamide (1.0 g, 6.02mmol) and THF (10 mL). Propyl magnesium chloride (2M in THF, 3.31 mL,6.62 mmol) is added and the mixture is stirred at room temperatureovernight. It is quenched with saturated sodium bicarbonate solution andextracted with dichloromethane. The combined organic layer is dried oversodium sulfate and concentrated in vacuo to afford1-pyridin-3-yl-butan-1-one as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δppm 1.03 (t, J=7.5 Hz, 3H), 1.74-1.87 (m, 2H), 2.97 (t, J=7.3 Hz, 2H),7.42 (dd, J=8.0, 4.9 Hz, 1H), 8.24 (dt, J=8.0, 2.0, 1.9 Hz, 1H), 8.78(dd, J=4.9, 2.0 Hz, 1H), 9.18 (d, J=2.0 Hz, 1H).

(c) 3-Ethyl-2-pyridin-3-yl-1H-indole

A flask is charged with phenylhydrazine (0.873 g, 6.46 mmol) and EtOH(14 mL). 1-Pyridin-3-yl-butan-1-one (0.914 g, 6.13 mmol) is added andthe reaction is refluxed for 1 h. After cooling to room temperature, HCl(4M in 1,4-dioxane, 6.45 mL, 25.83 mmol) is added. The reaction mixtureis refluxed for 4 h. After cooling to room temperature, the precipitateformed is filtered to afford 3-ethyl-2-pyridin-3-yl-1H-indole as ayellow solid. MS (ESI) m/z 223.0 (M+H)⁺.

(d)2-Methanesulfonyl-5-(3-ethyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzonitrile

3-Ethyl-2-pyridin-3-yl-1H-indole and2-methanesulfonyl-5-(3-ethyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzonitrile(Example 23d) are processed according to the method described in Example11 to give2-methanesulfonyl-5-(3-ethyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzonitrile.¹H NMR (400 MHz, MeOD) δ ppm 1.27 (t, J=7.6 Hz, 3H), 2.77 (q, J=7.6 Hz,2H), 3.27 (s, 3H), 5.49 (s, 2H), 7.14-7.31 (m, 3H), 7.37 (d, J=8.1 Hz,1H), 7.49 (s, 1H), 7.57 (dd, J=7.8, 5.1 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H),7.86 (dt, J=7.8, 1.8 Hz, 1H), 8.03 (d, J=8.3 Hz, 1H), 8.51 (d, J=2.0 Hz,1H), 8.62 (dd, J=4.9, 1.4 Hz, 1H). HRMS (ESI) m/z 416.1424 [(M+H)⁺Calcdfor C₂₄H₂₂N₃O₂S: 416.1433].

Example 253-Fluoro-4-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile

A flask is charged with 3-methyl-2-pyridin-3-yl-1H-indole hydrochloride(Example 1, 0.080 g, 0.326 mmol) and DMF (1.5 mL), and 60% NaH inmineral oil (0.028 g, 0.719 mmol) is added. The mixture is stirred atroom temperature for 20 min, followed by addition of4-bromomethyl-3-fluoro-benzonitrile (0.175 g, 0.817 mmol). The reactionmixture stirred at room temperature for 30 min. The residue is dilutedwith DMF (1.5 mL), filtered and purified by reverse phase HPLC withXbridge Shield RP18 column and a 0.1% aqueous NH₄OH in acetonitrilegradient to afford3-fluoro-4-(3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzonitrile as ayellow solid. ¹H NMR (400 MHz, MeOD) δ ppm 2.32 (s, 3H), 5.47 (s, 2H),6.62 (t, J=7.6 Hz, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.27 (t, J=7.6 Hz, 1H),7.38 (d, J=8.1 Hz, 2H), 7.50 (d, J=9.9 Hz, 1H), 7.56 (dd, J=7.8, 4.8 Hz,1H), 7.68 (d, J=7.8 Hz, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H), 8.52 (s, 1H),8.60 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 342.1394 [(M+H)⁺Calcd forC₂₂H₁₇FN₃: 342.1407].

Example 26 3-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile

3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1) and3-bromomethyl-benzonitrile are processed according to the methoddescribed in Example 25 to give3-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile. ¹H NMR(400 MHz, MeOD) δ ppm 2.33 (s, 3H), 5.41 (s, 2H), 7.08 (d, J=8.1 Hz,1H), 7.16 (s, 1H), 7.20 (t, J=7.2 Hz, 1H), 7.27 (ddd, J=7.6, 1.0 Hz,1H), 7.37 (d, J=5.8 Hz, 1H), 7.38-7.42 (m, 1H), 7.54-7.57 (m, 1H), 7.57(s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.85 (dt, J=7.8, 1.9 Hz, 1H), 8.50 (d,J=2.0 Hz, 1H), 8.60 (dd, J=4.8, 1.5 Hz, 1H). HRMS (ESI) m/z 324.1491[(M+H)⁺Calcd for C₂₂H₁₈N₃: 324.1501].

Example 27 4-(3-Methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile

3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1) and4-bromomethyl-benzonitrile are processed according to the methoddescribed in Example 25 to give4-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile. ¹H NMR(400 MHz, MeOD) δ ppm 2.32 (s, 3H), 5.43 (s, 2H), 6.99 (d, J=8.6 Hz,2H), 7.13-7.21 (m, 1H), 7.25 (ddd, J=7.6, 1.3 Hz, 1H), 7.34 (d, J=8.1Hz, 1H), 7.54 (dd, J=8.0, 4.9 Hz, 2H), 7.58 (d, J=8.3 Hz, 1H), 7.67 (d,J=7.6 Hz, 1H), 7.84 (dt, J=7.9, 2.0 Hz, 1H), 8.50 (d, J=1.5 Hz, 1H),8.59 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 324.1501 [(M+1-1)⁺Calcd forC₂₂H₁₈N₃: 324.1501].

Example 281-(2-Fluoro-4-methoxy-benzyl)-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride

3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1) and4-bromomethyl-2-fluoro-1-methoxy-benzene are processed according to themethod described in Example 25 to give1-(2-fluoro-4-methoxy-benzyl)-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride. ¹H NMR (400 MHz, MeOD) δ ppm (HCl salt) 2.38 (s, 3H),3.82 (s, 3H), 5.35 (s, 2H), 6.54-6.62 (m, 2H), 6.94 (t, J=8.6 Hz, 1H),7.22 (ddd, J=7.5, 0.9 Hz, 1H), 7.33 (ddd, J=7.6, 1.1 Hz, 1H), 7.45 (d,J=8.3 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 8.12 (dd, J=8.2, 5.7 Hz, 1H),8.54 (dt, J=8.1, 1.6 Hz, 1H), 8.80-8.89 (m, 2H). HRMS (ESI) m/z 347.1568[(M+H)⁺Calcd for C₂₂H₂₀FN₂O: 347.1560].

Example 294-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid

4-(5-Chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester (Example 11, 200 mg, 0.51 mmol) in methanol (5 mL) is addedto 5M aqueous NaOH (1 mL, 5 mmol) and the mixture is stirred at roomtemperature for 5 h. Concentrated HCl (4.4 mL) is added to neutralizethe reaction mixture and the solvents are removed in vacuo. The residueis redissolved in methanol and purified by reverse phase HPLC withXbridge Shield RP18 column and a 0.1% NH₄OH in acetonitrile gradient toafford 4-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoicacid. ¹H NMR (400 MHz, MeOD) δ ppm 2.25 (s, 3H), 5.34 (s, 2H), 6.82 (d,J=8.1 Hz, 2H), 7.15 (dd, J=8.6, 2.0 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H),7.50 (dd, J=7.7, 4.9 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.78-7.80 (m, 1H),7.81 (d, J=8.1 Hz, 2H), 8.50 (s, 1H), 8.56 (br. s, 1H). HRMS (ESI) m/z377.1072 [(M+H)⁺Calcd for C₂₂H₁₈ClN₂O₂: 377.1057].

Example 304-(5-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid

5-Fluoro-3-methyl-2-pyridin-3-yl-1H-indole (Example 3) is processedaccording to the method in Example 11 to give4-(5-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester.4-(5-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester is processed according to the method described in Example29 to give4-(5-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid.¹H NMR (400 MHz, MeOD) δ ppm 2.25 (s, 3H), 5.36 (s, 2H), 6.88 (d, J=8.6Hz, 2H), 6.94-7.00 (m, 1H), 7.28-7.29 (m, 1H), 7.30-7.32 (m, 1H),7.49-7.53 (m, 1H), 7.78-7.82 (m, 1H), 7.82-7.86 (m, 2H), 8.47-8.49 (m,1H), 8.56 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 361.1360 [(M+H)⁺Calcdfor C₂₂H₁₈FN₂O₂: 361.1352].

Example 314-(6-Chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid

A mixture of 4- and 6-chloro-3-methyl-2-pyridin-3-yl-1H-indole (Example5) is processed according to the method in Example 11 to give4-(6-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester and4-(4-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester. This mixture is processed according to the methoddescribed in Example 29 to give4-(6-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidafter reverse-phase HPLC purification. ¹H NMR (400 MHz, MeOD) δ ppm (TFAsalt) 2.30 (s, 3H), 5.41 (s, 2H), 6.89 (d, J=8.6 Hz, 2H), 7.15 (dd,J=8.3, 1.8 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H),7.81-7.88 (m, 3H), 8.20-8.27 (m, 1H), 8.68 (br. s., 1H), 8.70-8.73 (m,1H). HRMS (ESI) m/z 377.1050 [(M+H)⁺Calcd for C₂₂H₁₈ClN₂O₂: 377.1057].

Example 324-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid

4-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester (Example 12) is processed according to the method describedin Example 29 to give4-(6-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid.¹H NMR (400 MHz, MeOD) δ ppm (TFA salt) 2.31 (s, 3H), 5.40 (s, 2H), 6.90(d, J=8.6 Hz, 2H), 6.93-7.00 (m, 1H), 7.15 (dd, J=10.0, 2.1 Hz, 1H),7.65 (dd, J=8.8, 5.3 Hz, 1H), 7.86 (d, J=8.6 Hz, 2H), 7.88-7.92 (m, 1H),8.27-8.31 (m, 1H), 8.70 (d, J=1.8 Hz, 1H), 8.72 (dd, J=5.6, 1.5 Hz, 1H).HRMS (ESI) m/z 361.1360 [(M+H)⁺Calcd for C₂₂H₁₈FN₂O₂: 361.1352].

Example 334-(4-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid

4-(4-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acidmethyl ester (Example 13) is processed according to the method describedin Example 29 to give4-(4-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.32 (s, 3H), 5.37 (s, 2H), 6.81-6.88(m, 3H), 7.08-7.15 (m, 1H), 7.26 (d, J=8.1 Hz, 1H), 7.50 (dd, J=7.8, 4.8Hz, 1H), 7.74 (d, J=8.3 Hz, 2H), 7.77-7.81 (m, 1H), 8.55 (d, J=1.5 Hz,1H), 8.62 (dd, J=4.9, 1.6 Hz, 1H). MS (ESI) m/z 361.09 (M+H)⁺.

Example 344-(5-Cyano-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid

5-Cyano-3-methyl-2-pyridin-3-yl-indole (Example 6) is processedaccording to the method described in Example 11 to give4-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid methylester. To a solution of4-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid methylester (80 mg, 0.21 mmol) in methanol (5 mL) and THF (5 mL) is added 1Maqueous lithium hydroxide (2.5 mL, 2.5 mmol) and the mixture is stirredovernight at ambient temperature. The volatiles are removed in vacuo andthe residue is redissolved in DMF and purified by Xbridge RP18 with agradient of 0.1% aqueous ammonium hydroxide in acetonitrile to give4-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.25 (s, 3H), 5.40 (s, 2H), 6.71 (d, J=8.1Hz, 2H), 7.47-7.55 (m, 2H), 7.66 (t, J=8.6 Hz, 3H), 7.79-7.83 (m, 1H),8.20 (d, J=1.3 Hz, 1H), 8.58 (d, J=1.5 Hz, 1H), 8.64 (dd, J=4.8, 1.5 Hz,1H). HRMS (ESI) m/z 368.1396 [(M+H)⁺Calcd for C₂₃H₁₈N₃O₂: 368.1399].

Example 35 3-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoicacid

3-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzonitrile(Example 14, 200 mg, 0.56 mmol) in acetic acid (3 mL) is added to a 20%HCl aqueous solution (3 mL). The reaction mixture is refluxed for 3days. The volatiles are removed in vacuo and the residue is redissolvedin methanol and purified by reverse phase HPLC with Xbridge Shield RP18and a gradient of 0.1% NH₄OH in acetonitrile to give3-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.21 (s, 3H), 5.36 (s, 2H), 6.83 (d, J=7.1Hz, 1H), 7.13-7.23 (m, 2H), 7.43-7.52 (m, 3H), 7.64-7.70 (m, 2H),7.74-7.81 (m, 1H), 8.55 (s, 1H), 8.61-8.62 (m, 1H). HRMS (ESI) m/z377.1058 [(M+H)⁺ Calcd for C₂₂H₁₈ClN₂O₂: 377.1057].

Example 36 (a) 4-Bromomethyl-2,6-dimethyl-benzoic acid ethyl ester

Ethyl 2,4,6-trimethylbenzene (4.20 g, 21.41 mmol) and N-bromosuccinimide(4.23 g, 23.55 mmol) are taken up in carbon tetrachloride (200 mL), andbenzoyl peroxide (0.53 g, 2.14 mmol) is added. The suspension is heatedto reflux. After 4 h, the mixture is diluted with dichloromethane,washed with saturated aqueous sodium bicarbonate, water and brine, driedand concentrated in vacuo. The residue is purified by silica gel flashchromatography (heptane-ethyl acetate, 1 to 5%) to give partiallypurified 4-bromomethyl-2,6-dimethyl-benzoic acid ethyl ester, which istaken in the next step without further purification.

(b)2,6-Dimethyl-4-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoicacid ethyl ester

5-Chloro-3-methyl-2-pyridin-3-yl-1H-indole (Example 2, 1.350 g, 4.659mmol) is suspended in THF (40 mL) and cooled to 0° C. KHMDS (0.5M intoluene, 32.6 mL, 16.3 mmol) is added dropwise. After 1 h,4-bromomethyl-2,6-dimethyl-benzoic acid ethyl ester (4.95 g, 18.2 mmol)in THF (10 mL) is added dropwise. The mixture is allowed to warm to roomtemperature overnight. The mixture is then quenched with saturatedaqueous ammonium chloride and diluted with dichloromethane. The aqueousphase is extracted with ethyl acetate, dried over MgSO₄, filtered andconcentrated in vacuo. Purification of the residue by silica gelchromatography (dichloromethane-methanol, 1:0 to 99:1 to 49:1 to 97:3)affords2,6-dimethyl-4-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoicacid ethyl ester as an orange solid. MS (ESI) m/z 399 (M+H)⁺.

(c)2,6-Dimethyl-4-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoicacid

To a refluxing solution of lithium iodide (0.218 g, 1.626 mmol) in2,6-lutidine (5 mL) is added2,6-dimethyl-4-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoicacid ethyl ester (0.176 g, 0.407 mmol). The reaction is refluxedovernight. It is cooled to room temperature, acidified to pH 1 using 1Maqueous HCl solution and extracted with dichloromethane. The organiclayer is dried over sodium sulfate and concentrated in vacuo. Theresidue is purified by reverse phase HPLC with Xbridge Shield RP18column and a 0.1% aqueous NH₄OH in acetonitrile gradient to afford2,6-dimethyl-4-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoicacid as a solid. ¹H NMR (400 MHz, MeOD) δ ppm 2.22 (s, 6H), 2.28 (s,3H), 5.22 (s, 2H), 6.49 (s, 2H), 7.15 (dd, J=8.6, 2.0 Hz, 1H), 7.30 (d,J=8.8 Hz, 1H), 7.51-7.57 (m, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.81 (dt,J=8.1, 2.0, 1.8 Hz, 1H), 8.58 (d, J=1.3 Hz, 1H), 8.61 (dd, J=4.9, 1.6Hz, 1H). HRMS (ESI) m/z 405.1379 [(M+H)⁺Calcd for C₂₄H₂₁CIN₂O₂:405.1370].

Example 375-Chloro-3-methyl-2-pyridin-3-yl-1-[4-(2H-tetrazol-5-yl)-benzyl]-1H-indole

To a solution of4-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzonitrile(Example 17, 179 mg, 0.5 mmol) in DMF (5 mL) is added sodium azide (97mg, 1.5 mmol) and ammonium chloride (80 mg, 1.5 mmol) and the mixture isheated to 120° C. The reaction mixture is cooled to room temperature andfiltered. The filtrate is purified by reverse phase HPLC with XbridgeC18 and a gradient of 0.1% NH₄OH in acetonitrile to give5-chloro-3-methyl-2-pyridin-3-yl-1-[4-(2H-tetrazol-5-yl)-benzyl]-1H-indole.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.21 (s, 3H), 5.34 (s, 2H), 6.81 (d,J=8.1 Hz, 2H), 7.11 (br. s, 1H), 7.17 (dd, J=8.7, 2.1 Hz, 1H), 7.48-7.53(m, 2H), 7.67 (d, J=2.0 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.80-7.84 (m,1H), 8.60 (d, J=1.5 Hz, 1H), 8.62 (dd, J=4.8, 1.5 Hz, 1H). HRMS (ESI)m/z 401.1276 [(M+H)⁺Calcd for C₂₂H₁₈N₆Cl: 401.1281].

Example 38 3-(3-Methyl-2-pyridin-3-yl-indole-1-carbonyl)-benzonitrile

A flask is charged with 3-methyl-2-pyridin-3-yl-1H-indole hydrochloride(Example 1, 0.100 g, 0.408 mmol) in THF (2.5 mL) and cooled to 0° C.KHMDS (0.5 M in toluene, 1.8 mL, 0.898 mmol) is added and the mixture isstirred at room temperature for 30 min, followed by addition of3-cyano-benzoyl chloride (0.135 g, 0.817 mmol). The reaction mixture isstirred for 0.5 h, then quenched with saturated ammonium chloride andextracted with ethyl acetate. The organic layer is dried over sodiumsulfate and concentrated in vacuo. The residue is purified by reversephase HPLC with Xbridge Shield RP18 column and a 0.1% aqueous NH₄OH inacetonitrile gradient to afford3-(3-methyl-2-pyridin-3-yl-indole-1-carbonyl)-benzonitrile product as ayellow solid. ¹H NMR (400 MHz, MeOD) δ ppm 2.31 (s, 3H), 7.32 (ddd,J=7.9, 4.9, 0.9 Hz, 1H), 7.37-7.44 (m, 2H), 7.66-7.70 (m, 4H), 7.71-7.76(m, 2H), 7.85-7.91 (m, 1H), 8.37 (dd, J=5.1, 1.5 Hz, 1H), 8.46 (dd,J=2.3, 0.8 Hz, 1H). HRMS (ESI) m/z 338.1293 [(M+H)⁺Calcd for C₂₂H₁₆N₃O:338.1293].

Example 39 4-(3-Methyl-2-pyridin-3-yl-indole-1-carbonyl)-benzonitrile

4-Cyano-benzoyl chloride is processed according to the method describedin Example 38 to give4-(3-methyl-2-pyridin-3-yl-indole-1-carbonyl)-benzonitrile. ¹H NMR (400MHz, MeOD) δ ppm 2.32 (s, 3H), 7.32 (dd, J=7.8, 5.1 Hz, 1H), 7.37-7.45(m, 2H), 7.49 (t, J=7.8 Hz, 1H), 7.66-7.79 (m, 3H), 7.79-7.83 (m, 1H),7.86-7.93 (m, 2H), 8.34 (dd, J=4.8, 1.5 Hz, 1H), 8.47 (d, J=1.5 Hz, 1H).HRMS (ESI) m/z 338.1292 [(M+H)⁺Calcd for C₂₂H₁₆N₃O: 338.1293].

Example 40 (3-Methyl-2-pyridin-3-yl-indol-1-yl)-phenyl-methanone

3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride and benzoyl chloride areprocessed according to the method described in Example 38 to give(3-methyl-2-pyridin-3-yl-indol-1-yl)-phenyl-methanone. ¹H NMR (400 MHz,MeOD) δ ppm 2.33 (s, 3H), 7.26-7.40 (m, 5H), 7.45-7.52 (m, 1H), 7.57 (d,J=1.3 Hz, 1H), 7.59 (s, 1H), 7.63 (dd, J=7.1, 1.3 Hz, 1H), 7.68-7.73 (m,1H), 7.75 (dt, J=7.8, 1.9 Hz, 1H), 8.33 (dd, J=5.1, 1.5 Hz, 1H), 8.47(d, J=1.3 Hz, 2H). HRMS (ESI) m/z 313.1337 [(M+H)⁺Calcd for C₂₁H₁₇N₂O:313.1341].

Example 413-(5-Cyano-3-methyl-2-pyridin-3-yl-indole-1-carbonyl)-benzonitrile

KHMDS (0.5 M in toluene, 1.46 mL, 0.73 mmol) is added to a solution of3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6, 122 mg,0.480 mmol) in THF (10 mL) at room temperature. After 5 min,3-cyanobenzoyl chloride (178 mg, 1.08 mmol) is added. The mixture isstirred under N₂ for 1 h, whereupon aqueous ammonium chloride (0.5 mL)is added. The solvents are removed in vacuo and the residue is purifiedby Xbridge RP18 with a 0.1% aqueous ammonium hydroxide in acetonitrilegradient to give1-(3-cyano-benzoyl)-3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹HNMR (400 MHz, CDCl₃) δ ppm 2.35 (s, 3H), 7.37-7.44 (m, 1H), 7.47-7.52(m, 1H), 7.60-7.64 (m, 1H), 7.68-7.83 (m, 5H), 8.01 (d, J=1.5 Hz, 1H),8.51 (d, J=4.5 Hz, 1H), 8.53 (s, 1H). HRMS (ESI) m/z 363.1247[(M+H)⁺Calcd for C₂₃H₁₅N₄O: 363.1246].

Example 42 1-(3-Cyano-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 210mg, 0.96 mmol) in THF (20 mL) at room temperature is added 0.5 M KHMDSin toluene (4.10 mL, 2.05 mmol). After 30 min, 3-cyanobenzoyl chloride(510 mg, 3.08 mmol) is added. The mixture is stirred under N₂ overnight.The reaction is quenched with aqueous ammonium chloride and thevolatiles are removed in vacuo. The residue is redissolved indichloromethane and poured into saturated aqueous sodium bicarbonate(100 mL). Extraction with dichloromethane, drying over sodium sulfatefollowed by concentration affords a residue which is purified on anXBridge RP18 using a 0.1% ammonium hydroxide in acetonitrile gradient.Further purification by silica gel flash chromatography (heptane-ethylacetate, 3:2 to 2:3) affords1-(3-cyano-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.20 (d, J=0.5 Hz, 1H), 7.22-7.26 (m, 1H), 7.55 (t,J=7.8 Hz, 1H), 7.73-7.79 (m, 2H), 7.84 (d, 1H), 7.92-7.98 (m, 2H), 8.11(t, J=1.5 Hz, 1H), 8.29-8.33 (m, 1H), 8.39 (dd, J=4.8, 1.5 Hz, 1H), 8.60(dd, J=2.3, 0.8 Hz, 1H). HRMS (ESI) m/z 349.1106 [(M+H)⁺Calcd forC₂₂H₁₃N₄O: 349.1089].

Example 43 4-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acidmethyl ester

To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 240mg, 1.09 mmol) in THF (10 mL) at room temperature is added 0.5 M KHMDSin toluene (4.0 mL, 2.0 mmol). After 30 min, 4-chlorocarbonyl-benzoicacid methyl ester (400 mg, 2.0 mmol) is added. The mixture is stirredunder N₂ for 1 h. The reaction is quenched with aqueous sodiumbicarbonate and the volatiles are removed in vacuo. Purification bysilica gel flash chromatography using a heptane-ethyl acetate gradientaffords 4-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid methylester. ¹H NMR (400 MHz, MeOD) δ ppm 3.90 (s, 3H), 7.12 (s, 1H), 7.26(dd, J=8.0, 4.9 Hz, 1H), 7.63-7.72 (m, 3H), 7.77-7.81 (m, 1H), 7.91-7.96(m, 3H), 8.17 (d, J=1.5 Hz, 1H), 8.32 (dd, J=4.8, 1.5 Hz, 1H), 8.56 (d,J=2.3 Hz, 1H). HRMS (ESI) m/z 382.1186 [(M+H)⁺Calcd for C₂₃H₁₆N₃O₃:382.1192].

Example 44 (a) 4-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acidtert-butyl ester

To 2-pyridin-3-yl-1H-indole-5-carbonitrile (575 mg, 2.62 mmol),4-(butoxycarbonyl)benzoic acid (700 mg, 3.15 mmol) and DMAP (780 mg,3.93 mmol) in DMF (30 mL) is added DCC (811 mg, 3.93 mmol). The reactionis stirred for 3 days and the mixture is poured into water (50 mL) andextracted with ethyl acetate, dried over Na₂SO₄ and concentrated. Theresidue is purified by silica gel flash chromatography (ethylacetate-heptane gradient) to give4-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid tert-butylester as a white solid. MS (ESI) m/z 424 (M+H)⁺.

(b) 4-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid

4-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid tert-butylester (100 mg) is dissolved in TFA (3 mL) and stirred at ambienttemperature for 1 h. The solvent is removed in vacuo and the residue istriturated with diethyl ether twice. The residue is purified by reversephase H PLC with Sunfire C18 and a gradient of acetonitrile in 0.1%aqueous TFA to afford4-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm (TFA salt) 7.24 (s, 1H), 7.28(dd, J=7.9, 4.9 Hz, 1H), 7.73-7.77 (m, 4H), 7.81 (dt, J=8.1, 1.9, 1.8Hz, 1H), 7.87-7.91 (m, 2H), 8.32 (t, J=1.1 Hz, 1H), 8.41 (dd, J=4.9, 1.6Hz, 1H), 8.63-8.65 (m, 1H), 13.40 (br. s., 1H). HRMS (ESI) m/z 366.0868[(M+H)⁺Calcd for C₂₂H₁₄N₃O₃: 366.0879].

Example 451-(4-cyano-3-methyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

4-Cyano-3-methyl-benzoic acid is synthesized based on the methoddescribed in patent EP1512687A1. To a solution of2-pyridin-3-yl-1H-indole-5-carbonitrile (20 mg, 0.09 mmol),4-dimethylaminopyridine (22 mg, 0.01 mmol) and 4-cyano-3-methyl-benzoicacid (29 mg, 0.18 mmol) at 0° C. in dichloromethane (2 mL) is added DCC(38 mg, 0.18 mmol). After stirring for 10 min the reaction is warmed toroom temperature. A precipitate forms and stirring is continued for 16h. The mixture is filtered and the filtrate is diluted withdichloromethane (10 mL), washed with water and a saturated sodiumchloride solution. The combined organic extracts are dried over sodiumsulfate, filtered, and concentrated. The resulting residue is purifiedby silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:1)to furnish1-(4-cyano-3-methyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹HNMR (400 MHz, CDCl₃) δ ppm 2.47 (s, 3H), 6.91 (s, 1H), 7.14 (dd, J=8.0,4.9 Hz, 1H), 7.43-7.48 (m, 2H), 7.49-7.54 (m, 2H), 7.61 (dd, J=8.7, 1.6Hz, 1H), 7.93 (d, J=8.6 Hz, 1H), 8.03 (d, J=1.0\Hz, 1H), 8.44 (dd,J=4.8, 1.5 Hz, 1H), 8.55 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 363.1245[(M+H)⁺: Calcd for C₂₃H₁₆N₄O: 363.1246].

Example 46 3-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acidtert-butyl ester

Isophthalic acid mono-tert-butyl ester is processed according to themethod described in Example 45 to give3-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid tert-butylester. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.58 (s, 9H), 6.91 (s, 1H), 7.10(dd, J=7.6, 5.1 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.52-7.59 (m, 2H), 7.81(dt, J=7.9, 1.5, 1.3 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 8.02-8.06 (m, 2H),8.09 (t, J=1.6 Hz, 1H), 8.40 (d, J=3.4 Hz, 1H), 8.58 (d, J=1.8 Hz, 1H).HRMS (ESI) m/z 424.1662 [(M+H)⁺: Calcd for C₂₆H₂₂N₃O₃: 424.1661].

Example 47 1-(3-M ethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

3-Methylbenzoic acid is processed according to the method described inExample 45 to give1-(3-methyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹H NMR(400 MHz, CDCl₃) δ ppm 2.29 (s, 3H), 6.89 (s, 1H), 7.14 (dd, J=8.0, 4.9Hz, 1H), 7.19-7.24 (m, 1H), 7.27-7.31 (m, 1H), 7.39-7.44 (m, 2H),7.50-7.57 (m, 2H), 7.71 (d, J=8.6 Hz, 1H), 8.01 (d, J=1.0 Hz, 1H), 8.42(dd, J=4.8, 1.5 Hz, 1H), 8.62 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 338.1289[(M+H)⁺: Calcd for C₂₂H₁₆N₃O: 338.1293]

Example 481-(3,4-Dimethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

3,4-Dimethylbenzoic acid is processed according to the method describedin Example 45 to give1-(3,4-dimethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹H NMR(400 MHz, CDCl₃) δ ppm 2.21 (s, 3H), 2.26 (s, 3H), 6.89 (s, 1H), 7.10(d, J=7.8 Hz, 1H), 7.15 (dd, J=7.5, 5.2 Hz, 1H), 7.37-7.43 (m, 2H), 7.49(dd, J=8.6, 1.5 Hz, 1H), 7.57 (dt, J=8.3, 2.0, 1.6 Hz, 1H), 7.61 (d,J=8.8 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 8.44 (dd, J=4.8, 1.5 Hz, 1H),8.64 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 352.1458 [(M+H)⁺: Calcd forC₂₃H₁₈N₃O: 352.1450].

Example 49 1-(4-Methoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

4-Methoxybenzoic acid is processed according to the method described inExample 45 to give1-(4-methoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹H NMR(400 MHz, CDCl₃) δ ppm 3.83 (s, 3H), 6.81-6.85 (m, 2H), 6.90 (s, 1H),7.18 (dd, J=7.8, 3.0 Hz, 1H), 7.49 (dd, J=8.6, 1.5 Hz, 1H), 7.58-7.62(m, 2H), 7.62-7.66 (m, 2H), 8.01 (d, J=1.5 Hz, 1H), 8.46 (dd, J=4.8, 1.5Hz, 1H), 8.66 (d, J=3.0 Hz, 1H). HRMS (ESI) m/z 354.1225 [(M+H)⁺: Calcdfor C₂₂H₁₆N₃O₂: 354.1243].

Example 50 1-(3-Methoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

3-Methoxybenzoic acid is processed according to the method described inExample 45 to give1-(3-methoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹H NMR(400 MHz, CDCl₃) δ ppm 3.78 (s, 3H), 6.89 (s, 1H), 7.02 (ddd, J=8.2,2.6, 1.1 Hz, 1H), 7.13-7.18 (m, 3H), 7.23 (d, J=8.1 Hz, 1H), 7.52 (dd,J=8.6, 1.5 Hz, 1H), 7.57 (dt, J=8.0, 1.9 Hz, 1H), 7.69 (d, J=8.8 Hz,1H), 8.01 (d, J=1.0 Hz, 1H), 8.45 (dd, J=4.8, 1.5 Hz, 1H), 8.64 (d,J=2.3 Hz, 1H). HRMS (ESI) m/z 354.1231 [(M+H)⁺: Calcd for C₂₂H₁₆N₃O₂:354.1243].

Example 511-(3,4-Dimethoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

3,4-Dimethoxybenzoic acid is processed according to the method describedin Example 45 to give1-(3,4-dimethoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹HNMR (400 MHz, CDCl₃) δ ppm 3.87 (s, 3H), 3.90 (s, 3H), 6.75 (d, J=8.6Hz, 1H), 6.92 (s, 1H), 7.19 (dd, J=7.8, 4.3 Hz, 1H), 7.22 (dd, J=8.5,2.2 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.50 (dd, J=8.7, 1.6 Hz, 1H),7.58-7.63 (m, 2H), 8.02 (d, J=1.0 Hz, 1H), 8.47 (dd, J=4.8, 1.5 Hz, 1H),8.68 (dd, J=2.3, 0.8 Hz, 1H). HRMS (ESI) m/z 384.1349 [(M+H)⁺: Calcd forC₂₃H₁₈N₃O₃: 384.1348].

Example 52 1-(3-Ethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

3-Ethylbenzoic acid is processed according to the method described inExample 45 to give1-(3-ethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹H NMR (400MHz, CDCl₃) δ ppm 1.16 (t, J=7.6 Hz, 3H), 2.58 (q, J=7.6 Hz, 2H), 6.89(s, 1H), 7.12 (dd, J=8.0, 4.9 Hz, 1H), 7.22-7.25 (m, 1H), 7.29-7.33 (m,1H), 7.40 (s, 1H), 7.43-7.47 (m, 1H), 7.51-7.57 (m, 2H), 7.73 (d, J=8.8Hz, 1H), 8.02 (d, J=1.0 Hz, 1H), 8.42 (dd, J=4.8, 1.5 Hz, 1H), 8.63 (d,J=1.8 Hz, 1H). HRMS (ESI) m/z 352.1443 [(M−H)⁺: Calcd for C₂₃H₁₈N₃O:352.1450].

Example 531-(3,5-Dimethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 200mg, 0.913 mmol) at 0° C. in THF (6 mL) is added 60% sodium hydride (72mg, 1.826 mmol) and the mixture is stirred for 10 min at 0° C. Thereaction mixture is then warmed to room temperature and stirred for 30min. 3,5-Dimethyl-benzoyl chloride (460 mg, 2.740 mmol) in THF (2 mL) isadded dropwise at 0° C. and the reaction is stirred at room temperaturefor 1 h. The reaction is quenched by adding saturated sodiumbicarbonate. The THF is removed under vacuum, and the resulting residueis purified by silica gel flash chromatography (ethyl acetate-heptane,0:1 to 1:1). The resulting product is further purified by HPLC using anX-bridge RP18 and an acetonitrile-0.1% ammonia hydroxide gradient toyield 1-(3,5-dimethyl-benzoyl)-2-pyridine-3-yl-1H-indole-5-carbonitrile.¹H NMR (400 MHz, CDCl₃) δ ppm 2.25 (s, 6H), 6.88 (s, 1H), 7.10 (s, 1H),7.14 (dd, J=7.6, 5.3 Hz, 1H), 7.22 (s, 2H), 7.50-7.56 (m, 2H), 7.70 (d,J=8.8 Hz, 1H), 8.01 (s, 1H), 8.43 (dd, J=4.8, 1.5 Hz, 1H), 8.62 (s, 1H).HRMS (ESI) m/z 352.1452 [(M+H)⁺: Calcd for C₂₃H₁₈N₃O: 352.1450].

Example 54 (a) 5-Bromo-2-methyl-benzoic acid tert-butyl ester

To a suspension of anhydrous magnesium sulfate (4.5 g, 37.28 mmol) indichloromethane (37 mL) is added concentrated H₂SO₄ (516 μl, 9.302 mmol)and the mixture is stirred vigorously for 15 min.5-Bromo-2-methyl-benzoic acid (2 g, 9.302 mmol) is added, followed byt-butanol (4.39 mL, 46.51 mmol). The flask is capped tightly and stirredat room temperature for 24 h. After adding saturated sodium bicarbonate,the resulting solution is extracted with ethyl acetate. The organiclayer is washed with a saturated sodium chloride solution, dried oversodium sulfate, filtered and concentrated. The resulting residue ispurified by silica gel flash chromatography (ethyl acetate-heptane, 0:1to 3:7) to furnish 5-bromo-2-methyl-benzoic acid tert-butyl ester. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.59 (s, 9H), 2.51 (s, 3H), 7.08 (d, J=8.1Hz, 1H), 7.46 (dd, J=8.3, 2.3 Hz, 1H), 7.92 (d, J=2.3 Hz, 1H)

(b) 4-Methyl-isophthalic acid 3-tert-butyl ester

n-Butyllithium (1.6M in hexane, 1.29 mL, 1.975 mmol) is slowly added to5-bromo-2-methyl-benzoic acid tent-butyl ester (511 mg, 1.884 mmol) inTHF (18 mL) at −78° C. under N₂. The reaction mixture is stirred at −78°C. for 30 min. Carbon dioxide gas is bubbled through the solution untilthe solution color changes to orange. After stirring at −78° C. for 10min, the reaction mixture is warmed to room temperature. The reaction isquenched with saturated ammonium chloride, extracted with ethyl acetate,dried over sodium sulfate, filtered and concentrated. The resultingresidue is purified by silica gel flash chromatography (ethylacetate-heptane, 0:1 to 1:1) to furnish 4-methyl-isophthalic acid3-tent-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.62 (s, 9H), 2.65 (s,3H), 7.33 (d, J=7.83 Hz, 1H), 8.07 (dd, J=7.96, 1.89 Hz, 1H), 8.52 (d,J=2.02 Hz, 1H).

(c) 5-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-2-methyl-benzoic acidtert-butyl ester

4-methyl-isophthalic acid 3-tert-butyl ester is processed according tothe method described in Example 45 to give5-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-2-methyl-benzoic acidtert-butyl ester. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.57 (s, 9H), 2.55 (s,3H), 6.91 (s, 1H), 7.13 (dd, J=7.83, 4.29 Hz, 1H), 7.20 (d, J=8.08 Hz,1H), 7.53-7.58 (m, 2H), 7.66 (dd, J=7.96, 2.15 Hz, 1H), 7.76 (d, J=8.59Hz, 1H), 7.98 (d, J=2.02 Hz, 1H), 8.02 (d, J=1.01 Hz, 1H), 8.43 (dd,J=4.80, 1.52 Hz, 1H), 8.61 (d, J=2.27 Hz, 1H).

(d) 5-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-2-methyl-benzoic acid

5-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-2-methyl-benzoic acidtert-butyl ester is dissolved in trifluoroacetic acid (3 mL), andstirred at room temperature for 1 h. After removing the solvent, theresidue is purified by HPLC with an X-bridge Phenyl usingacetonitrile-0.1% trifluoroacetic acid as an eluent to yield5-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-2-methyl-benzoic acid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm (TFA salt) 2.59 (s, 3H), 7.32 (s, 1H),7.39-7.44 (m, 2H), 7.71-7.75 (m, 1H), 7.76-7.79 (m, 1H), 7.81 (dd,J=7.8, 2.0 Hz, 1H), 7.92 (dt, J=8.0, 1.8 Hz, 1H), 8.11 (d, J=2.0 Hz,1H), 8.38 (d, J=1.5 Hz, 1H), 8.52 (dd, J=5.0, 1.5 Hz, 1H), 8.74 (d,J=2.0 Hz, 1H). HRMS (ESI) m/z 382.1202 [(M+H)⁺Calcd for C₂₃H₁₆N₃O₃:382.1192].

Example 55 3-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid

3-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid tert-butylester (Example 46) is processed according to the method described inExample 54d to give5-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-2-methyl-benzoic acid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm (TFA salt) 7.16-7.21 (m, 2H), 7.43 (t,J=7.8 Hz, 1H), 7.67 (dd, J=8.7, 1.64 Hz, 1H), 7.71-7.75 (m, 2H), 7.82(dt, J=8.0, 1.5, 1.3 Hz, 1H), 7.97 (dt, J=7.8, 1.4 Hz, 1H), 8.00 (t,J=1.5 Hz, 1H), 8.25 (d, J=1.0 Hz, 1H), 8.32 (dd, J=4.8, 1.5 Hz, 1H),8.55 (d, J=1.6 Hz, 1H). HRMS (ESI) m/z 368.1040 [(M+H)⁺ Calcd forC₂₂H₁₄N₃O₃: 368.1035]

Example 561-(3-Cyano-benzenesulfonyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 300mg, 1.37 mmol) at 0° C. in DMF (12 mL) is added 60% sodium hydride (82mg, 2.06 mmol) and the mixture stirred for 10 min at 0° C. The reactionmixture is then warmed to room temperature and stirred for 30 min.3-Cyanobenzenesulfonyl chloride (552 mg, 2.74 mmol) in DMF (2 mL) isadded dropwise at 0° C. and the reaction is stirred at room temperaturefor 1 h. The reaction is quenched by adding water (1 mL). The resultingmixture is purified by HPLC X-bridge RP18 using acetonitrile-0.1%ammonia hydroxide as an eluent to yield1-(3-cyano-benzenesulfonyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.11 (s, 1H), 7.54 (dd, J=7.8, 4.8 Hz, 1H),7.66 (dd, J=8.1, 2.0 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.86 (dd, J=8.7,1.6 Hz, 1H), 7.94 (t, J=1.5 Hz, 1H), 7.98 (dt, J=8.2, 2.0, 1.8 Hz, 1H),8.16 (dd, J=7.6, 1.3 Hz, 1H), 8.19 (d, J=1.0 Hz, 1H), 8.34 (d, J=8.6 Hz,1H), 8.67 (d, J=2.8 Hz, 1H), 8.71 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI)m/z 385.0763 [(M+H)⁺Calcd for C₂₁H₁₃N₄O₂S: 385.0759].

Example 573-Methyl-1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

To a solution of 3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile(Example 6, 47 mg, 0.20 mmol) in THF (5 mL) at room temperature is addedKHMDS (0.5 M in toluene, 0.60 mL, 0.30 mmol) followed with(2-bromo-ethoxy)-benzene (90 mg, 0.45 mmol). The mixture is stirredunder N₂ for 2 days and aqueous ammonium chloride (1 mL) is added toquench the reaction. The volatiles are removed in vacuo and the residueis purified by silica gel flash chromatography (ethyl acetate-heptane,1:4 to 1:0) to give3-methyl-1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. ¹HNMR (400 MHz, CDCl₃) δ ppm 2.25 (s, 3H), 4.10 (t, J=5.2 Hz, 2H), 4.46(t, J=5.3 Hz, 2H), 6.66 (d, J=7.8 Hz, 2H), 6.93 (t, J=7.3 Hz, 1H),7.17-7.25 (m, 2H), 7.51-7.57 (m, 2H), 7.59-7.65 (m, 1H), 7.95 (d, J=8.6Hz, 1H), 7.98 (s, 1H), 8.74-8.79 (m, 2H). HRMS (ESI) m/z 354.1618[(M+H)⁺ Calcd for C₂₃H₂₀N₃O: 354.1606].

Example 58 1-(2-Phenoxy-ethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

(2-Bromo-ethoxy)-benzene and 2-pyridin-3-yl-1H-indole-5-carbonitrile(Example 8) are processed according to the method described in Example57 to give 1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile.¹H NMR (400 MHz, MeOD) δ ppm 4.19 (t, J=5.2 Hz, 2H), 4.67 (t, J=5.1 Hz,2H), 6.63 (d, J=7.8 Hz, 2H), 6.77 (s, 1H), 6.84 (t, J=7.5 Hz, 1H),7.10-7.17 (m, 2H), 7.53 (dd, J=8.6, 1.8 Hz, 1H), 7.55-7.60 (m, 1H), 7.77(d, J=8.6 Hz, 1H), 8.05 (s, 1H), 8.08-8.13 (m, 1H), 8.63 (dd, J=4.9, 1.6Hz, 1H), 8.79 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 340.1453 [(M+H)⁺Calcdfor C₂₂H₁₈N₃O: 340.1450].

Example 59 3-Methyl-1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole

A flask is charged with 3-methyl-2-pyridin-3-yl-1H-indole hydrochloride(Example 1, 0.100 g, 0.408 mmol) and DMF (2 mL). The solution is cooledto 0° C. and 60% NaH in mineral oil (0.036 g, 0.898 mmol) is added. Themixture is stirred at room temperature for 20 min followed by additionof (2-bromo-ethoxy)-benzene (0.205 mL, 1.021 mmol). The mixture isstirred at room temperature for 5 h, whereupon it is concentrated invacuo. The residue is purified by reverse phase HPLC with Xbridge ShieldRP18 column and a gradient of 0.1% aqueous TFA in acetonitrile to afford3-methyl-1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole as a yellowtrifluoro acetate salt. ¹H NMR (400 MHz, MeOD) δ ppm (TFA salt) 2.29 (s,3H), 4.18 (t, J=5.2 Hz, 2H), 4.55 (t, J=5.1 Hz, 2H), 6.64 (d, J=7.8 Hz,2H), 6.87 (t, J=7.5 Hz, 1H), 7.11-7.22 (m, 3H), 7.33 (ddd, J=7.6, 1.1Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.96 (dd,J=8.0, 5.4 Hz, 1H), 8.44 (dt, J=8.0, 1.9, 1.8 Hz, 1H), 8.77 (dd, J=5.6,1.3 Hz, 1H), 8.89 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 329.1646[(M+H)⁺Calcd for C₂₂H₂₁N₂O: 329.1654].

Example 60 (a) 3-(2-Bromo-ethoxy)-benzoic acid methyl ester

A flask is charged with 3-hydroxybenzoic acid methyl ester (2.54 g, 16.0mmol) and acetone (50 mL). 1,2-Dibromo-ethane (5.69 mL, 66.0 mmol) andpotassium carbonate (2.76 g, 19.0 mmol) are added and the mixture isrefluxed for 24 h. The reaction mixture is then cooled to roomtemperature. The solids are filtered off and the filtrate concentratedin vacuo. The residue is purified by silica gel flash chromatography(heptane-ethyl acetate, 3:1) to afford 3-(2-bromo-ethoxy)-benzoic acidmethyl ester as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.66 (t,J=6.2 Hz, 2H), 3.93 (s, 3H), 4.35 (t, J=6.2 Hz, 2H), 7.14 (m, 1H) 7.37(m, 1H) 7.57 (m, 1H) 7.68 (m, 1H).

(b) 3-[2-(5-Cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoicacid methyl ester

3-(2-Bromo-ethoxy)-benzoic acid methyl ester and5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl (Example 6) are processedaccording to the method described in Example 59 to give3-[2-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acidmethyl ester. ¹H NMR (400 MHz, MeOD) δ ppm 2.26 (s, 3H), 3.90 (s, 3H),4.22 (t, J=4.9 Hz, 2H), 4.60 (t, J=5.1 Hz, 2H), 6.91 (dd, J=7.8, 2.3 Hz,1H), 7.21-7.24 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.52-7.59 (m, 2H), 7.65(dd, J=7.8, 5.1 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.98-8.09 (m, 2H),8.56-8.77 (m, 2H). HRMS (ESI) m/z 412.1664 [(M+H)⁺Calcd for C₂₅H₂₂N₃O₃:412.1661].

Example 61 (a) 4-(2-Bromo-ethoxy)-benzoic acid methyl ester

4-Hydroxybenzoic acid methyl ester is processed according to the methoddescribed in Example 60a to give 4-(2-Bromo-ethoxy)-benzoic acid methylester.

(b) 4-[2-(5-Cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoicacid methyl ester

4-(2-Bromo-ethoxy)-benzoic acid methyl ester and5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl (Example 6) are processedaccording to the method described in Example 59 to give4-[2-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acidmethyl ester. ¹H NMR (400 MHz, MeOD) δ ppm 2.28 (s, 3H), 3.87 (s, 3H),4.24 (t, J=5.1 Hz, 2H), 4.61 (t, J=5.1 Hz, 2H), 6.73-6.79 (m, 2H), 7.58(dd, J=8.5, 1.6 Hz, 1H), 7.66 (ddd, J=7.9, 5.0, 0.8 Hz, 1H), 7.77 (dd,J=8.6, 0.5 Hz, 1H), 7.85-7.88 (m, 1H), 7.88-7.90 (m, 1H), 8.03 (dt,J=8.1, 1.9, 1.8 Hz, 1H), 8.07 (dd, J=1.5, 0.6 Hz, 1H), 8.52-8.84 (m,2H). HRMS (ESI) m/z 412.1660 [(M+H)⁺Calcd for C₂₅H₂₂N₃O₃: 412.1661].

Example 624-[2-(5-Cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid

A flask is charged with4-[2-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acidmethyl ester (Example 61, 0.150 g, 0.36 mmol) in MeOH (5 mL). Aqueouslithium hydroxide (1 M, 0.912 mL, 0.912 mmol) is added and the mixtureis refluxed overnight. The reaction mixture is then acidified to pH 1using 1 M aqueous HCl solution and the methanol is removed in vacuo. Theresulting solution is extracted with ethyl acetate. The organic layer isdried over sodium sulfate, filtered and concentrated. The resultingresidue is purified by silica gel flash chromatography(dichloromethane-methanol, 9:1) to afford4-[2-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acidas a white solid. ¹H NMR (400 MHz, MeOD) δ ppm 2.27 (s, 3H), 4.22 (t,J=5.1 Hz, 2H), 4.60 (t, J=5.2 Hz, 2H), 6.72 (d, J=8.8 Hz, 2H), 7.57 (dd,J=8.6, 1.5 Hz, 1H), 7.62-7.72 (m, 1H), 7.76 (d, J=8.6 Hz, 1H), 7.86 (d,J=8.6 Hz, 2H), 8.02 (d, J=7.8 Hz, 1H), 8.07 (s, 1H), 8.72 (br. s., 2H).HRMS (ESI) m/z 398.1487 [(M+H)⁺Calcd for C₂₄H₂₀N₃O₃: 398.1505].

Example 63 (a)4-[2-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acidmethyl ester

4-(2-Bromo-ethoxy)-benzoic acid methyl ester (Example 61a) and5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl (Example 2) are processedaccording to the method described in Example 59 to give4-[2-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acidmethyl ester. MS (ESI) m/z 421.01.

(b) 4-[2-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoicacid

4-[2-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acidmethyl ester is processed according to the method described in Example62 to give4-[2-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid.¹H NMR (400 MHz, MeOD) δ ppm 2.22 (s, 3H), 4.21 (t, J=5.1 Hz, 2H), 4.54(t, J=5.1 Hz, 2H), 6.73 (d, J=8.8 Hz, 2H), 7.25 (dd, J=8.7, 2.1 Hz, 1H),7.56 (d, J=8.6 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.61-7.67 (m, 1H), 7.87(d, J=8.8 Hz, 2H), 7.99 (d, J=7.8 Hz, 1H), 8.68 (br. s., 2H); HRMS (ESI)m/z 407.1157 [(M+H)⁺Calcd for C₂₃H₂₀ClN₂O₃: 407.1162].

Example 64 2-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethanol

A flask is charged with 5-chloro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride (Example 2, 1.0 g, 3.58 mmol) and THF (20 mL) and cooledto 0° C. KHMDS (0.5 M in toluene, 17.9 mL, 8.95 mmol) is added and themixture is stirred at room temperature for 30 min, followed by additionof (2-chloro-ethoxy)-trimethylsilane (1.06 mL, 8.95 mmol). The reactionmixture is stirred for 48 h at 60° C. After cooling to room temperature,aqueous 1M HCl (30 mL) is added and the mixture is stirred at roomtemperature for 30 min, then washed with water and extracted with ethylacetate twice. The organic layer is dried over sodium sulfate andconcentrated in vacuo. The residue is purified by silica gel flashchromatography (heptane-ethyl acetate, 1:4) to afford2-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethanol as a solid. ¹HNMR (400 MHz, MeOD) δ ppm 2.22 (s, 3H), 3.69 (t, J=5.9 Hz, 2H), 4.18 (t,J=5.8 Hz, 2H), 7.21 (dd, J=8.6, 2.0 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H),7.57 (d, J=1.8 Hz, 1H), 7.61-7.67 (m, 1H), 8.01 (dt, J=7.9, 2.0 Hz, 1H),8.61-8.71 (m, 2H). HRMS (ESI) m/z 287.0953 [(M+H)⁺Calcd for C₁₆H₁₆ClN₂O:287.0951].

Example 65 2,2-Dimethyl-propionic acid5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester

A flask is charged with 5-chloro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride (Example 2, 1.0 g, 3.58 mmol) and THF (20 mL) and cooledto 0° C. KHMDS (0.5 M in toluene, 17.9 mL, 8.95 mmol) is added and themixture is stirred at room temperature for 30 min, followed by additionof 2,2-dimethyl-propionic acid chloromethyl ester (2.58 mL, 8.95 mmol).The reaction mixture is stirred at room temperature for 3.5 h, thenwashed with water and extracted with ethyl acetate twice. The organiclayer is dried over sodium sulfate and concentrated in vacuo. Theresidue is purified by silica gel flash chromatography (heptane-ethylacetate, 1:1) to afford an oil, which is taken up in diethyl ether. Afew drops of concentrated HCl are added. Evaporation of the solvent andlyophilization give 2,2-dimethyl-propionic acid5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester as a solid. ¹HNMR (400 MHz, MeOD) δ ppm (HCl salt) 1.12 (s, 9H), 2.27 (s, 3H), 6.06(s, 2H), 7.30 (dd, J=8.6, 2.0 Hz, 1H), 7.60 (s, 1H), 7.63 (d, J=2.3 Hz,1H), 7.74 (dd, J=7.8, 5.1 Hz, 1H), 8.01-8.16 (m, 1H), 8.64-8.79 (m, 2H).HRMS (ESI) m/z 357.1121 [(M+H)⁺Calcd for C₂₀H₂₂ClN₂O₂: 357.1127].

Example 66 2-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-methanol

A flask is charged with 2,2-dimethyl-propionic acid5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester (Example 65,0.607 g, 1.684 mmol) and dichloromethane (10 mL) and cooled to −78° C.DIBAL-H (1M in hexane, 4.21 mL, 4.21 mmol) is added and the mixture isstirred at −78° C. for 1 h. The reaction is quenched with MeOH (1 mL)and then washed with saturated aqueous sodium potassium tartrate andextracted with ethyl acetate. The organic layer is dried over sodiumsulfate and concentrated in vacuo, to give a residue which is purifiedby silica gel flash chromatography (heptane-ethyl acetate, 3:7) toafford (5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-methanol as a whitecolor solid. ¹H NMR (400 MHz, MeOD) δ ppm 2.27 (s, 3H), 5.46 (s, 2H),7.25 (dd, J=8.6, 2.0 Hz, 1H), 7.55 (s, 1H), 7.58 (s, 1H), 7.59 (d, J=2.0Hz, 1H), 7.62-7.67 (m, 1H), 8.08 (dt, J=8.1, 2.0, 1.8 Hz, 1H), 8.66 (dd,J=4.9, 1.6 Hz, 1H), 8.75 (d, J=1.3 Hz, 1H). HRMS (ESI) m/z 273.0807[(M+H)⁺Calcd for C₁₅H₁₄ClN₂O: 273.0795].

Example 67 2-(5-Cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-methanol

A mixture of 5-cyano-3-methyl-2-pyridin-3-yl-indole (Example 6, 0.200 g,0.587 mmol) in formaldehyde (4.0 mL) is refluxed for 5 h. The reactionis cooled to room temperature, diluted with ethyl acetate and washedwith water. The organic layer is dried over sodium sulfate andconcentrated in vacuo, to give a residue which is purified by silica gelflash chromatography (dichloromethane-acetonitrile, 7:3) and furtherpurified by reverse phase H PLC with an Xbridge Shield RP18 column and agradient of 0.1% aqueous TFA in acetonitrile to afford2-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-methanol as thetrifluoroacetate salt. ¹H NMR (400 MHz, MeOD) δ ppm (TFA salt) 2.37 (s,3H), 5.54 (s, 2H), 7.61 (dd, J=8.6, 1.5 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H),8.01 (dd, J=7.3, 5.3 Hz, 1H), 8.12 (d, J=1.0 Hz, 1H), 8.54 (dt, J=7.9,1.9 Hz, 1H), 8.85 (dd, J=5.4, 1.4 Hz, 1H), 9.01 (d, J=1.5 Hz, 1H). HRMS(ESI) m/z 264.1134 [(M+H)⁺ Calcd for C₁₆H₁₄N₃O: 264.1137].

Example 68 2,2-Dimethyl-propionic acid5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester

A flask is charged with 3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile(Example 6, 0.200 g, 0.856 mmol) and DMF (10 mL). The mixture is cooledto 0° C. and 60% NaH in mineral oil (0.086 g, 2.14 mmol) is added. Themixture is stirred at room temperature for 20 min followed by additionof 2,2-dimethyl-propionic acid chloromethyl ester (0.310 mL, 2.14 mmol).After stirring at room temperature for 1.5 h, the mixture is dilutedwith ethyl acetate and washed with water. The organic layer is driedover sodium sulfate and concentrated in vacuo. The residue is purifiedby reverse phase HPLC with Xbridge Shield RP18 column and a 0.1% aqueousNH₄OH in acetonitrile gradient to afford 2,2-dimethyl-propionic acid5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester product as awhite solid. ¹H NMR (400 MHz, MeOD) δ ppm 1.12 (s, 9H), 2.31 (s, 3H),6.10 (s, 2H), 7.62 (dd, J=8.5, 1.6 Hz, 1H), 7.68 (ddd, J=7.9, 5.0, 0.8Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 8.04 (dt, J=8.1, 2.0, 1.8 Hz, 1H), 8.09(d, J=1.0 Hz, 1H), 8.66-8.76 (m, 2H). HRMS (ESI) m/z 348.1700[(M+H)⁺Calcd for C₂₁H₂₂N₃O₂: 348.1712].

Example 69 (a) N-Hydroxymethyl-2,2-dimethyl-propionamide

A flask is charged with 2,2-dimethyl-propionamide (1.00 g, 9.98 mmol),p-formaldehyde (0.736 g, 9.98 mmol), and potassium carbonate (0.054 g,3.95 mmol). The reaction mixture is stirred at 75° C. for 16 h,whereupon it is cooled to room temperature and diluted with acetone.Filtration and concentration of the filtrate give a residue which ispurified by silica gel flash chromatography (heptane-ethyl acetate, 4:1)to afford N-hydroxymethyl-2,2-dimethyl-propionamide as a white solid. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.25 (s, 9H), 4.73 (d, J=7.1 Hz, 2H).

(b) N-Chloromethyl-2,2-dimethyl-propionamide

A flask is charged with N-hydroxymethyl-2,2-dimethyl-propionamide (0.500g, 3.81 mmol) and dichloromethane (4 mL). Oxalyl chloride (0.8 mL, 9.52mmol) is added and the reaction mixture is stirred at room temperaturefor 2 h. Concentration in vacuo givesN-chloromethyl-2,2-dimethyl-propionamide as a white solid. ¹H NMR (400MHz, CDCl₃) δ ppm 1.23 (s, 9H), 5.31 (s, 2H).

(c)N-(5-Cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-2,2-dimethyl-propionamide

N-Chloromethyl-2,2-dimethyl-propionamide and3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6) areprocessed according to the method described in Example 68 to giveN-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-2,2-dimethyl-propionamide.¹H NMR (400 MHz, MeOD) δ ppm 1.06 (s, 9H), 2.27 (s, 3H), 5.54 (s, 2H),7.55 (dd, J=8.6, 1.8 Hz, 1H), 7.66 (ddd, J=7.9, 5.0, 1.0 Hz, 1H), 7.81(d, J=8.6 Hz, 1H), 8.01-8.09 (m, 2H), 8.65-8.73 (m, 2H). HRMS (ESI) m/z347.1863 [(M+H)⁺Calcd for C₂₁H₂₃N₄O: 347.1872].

Example 70 (a) 1-Chloromethoxy-2,2-dimethyl-propane

A 2-neck flask is charged with formaldehyde (1.1 g, 36.8 mmol),2,2-dimethyl-propan-1-ol (2.5 g, 28.3 mmol) and toluene (50 mL). Thereaction mixture is cooled to −20° C. and HCl gas is bubbled through for30 min. Sodium sulfate (5.9 g) is added to the reaction mixture, whichis then stirred at −10° C. overnight, warmed to 0° C. and stirred foranother 5 h. The solids are filtered off and the filtrate isconcentrated in vacuo to afford 1-chloromethoxy-2,2-dimethyl-propane asa colorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.95 (s, 9H), 3.36 (s,2H), 5.54 (s, 2H).

(b)1-(2,2-Dimethyl-propoxymethyl)-3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile

3-Methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6) and1-chloromethoxy-2,2-dimethyl-propane are processed according to themethod described in Example 68 to give1-(2,2-dimethyl-propoxymethyl)-3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile.¹H NMR (400 MHz, MeOD) δ ppm 0.84 (s, 9H), 2.33 (s, 3H), 3.04 (s, 2H),5.48 (s, 2H), 7.59 (dd, J=8.6, 1.5 Hz, 1H), 7.66 (ddd, J=8.0, 4.9, 1.0Hz, 1H), 7.77 (dd, J=8.6, 0.5 Hz, 1H), 8.07 (dt, J=7.8, 1.9 Hz, 1H),8.09 (dd, J=1.5, 0.8 Hz, 1H), 8.70 (dd, J=4.9, 1.6 Hz, 1H), 8.75 (dd,J=2.3, 0.8 Hz, 1H). HRMS (ESI) m/z 334.1914 [(M+H)⁺Calcd for C₂₁H₂₄N₃O:334.1919].

Example 71 (5-Cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-acetic acidtert-butyl ester

3-Methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6) andtert-butyl bromoacetate are processed according to the method describedin Example 68 to give(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-acetic acid tert-butylester. ¹H NMR (400 MHz, MeOD) δ ppm 1.38 (s, 9H), 2.31 (s, 3H), 4.83 (s,2H), 7.56 (d, J=1.3 Hz, 2H), 7.66 (ddd, J=7.8, 4.9, 0.9 Hz, 1H), 7.95(dt, J=7.8, 1.9 Hz, 1H), 8.09 (s, 1H), 8.63 (d, J=1.3 Hz, 1H), 8.71 (dd,J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 348.1719 [(M+H)⁺ Calcd forC₂₁H₂₂N₃O₂: 348.1712].

Example 72 (a) Chloromethoxy-acetic acid ethyl ester

Chloromethoxy-acetic acid ethyl ester is prepared according to themethod described in Heterocycles 2005, 65, 1967. A 2-neck flask ischarged with formaldehyde (0.747 g, 24.9 mol), hydroxy-acetic acid ethylester (2.0 g, 19.2 mmol) and toluene (50 mL). The reaction mixture iscooled to −20° C., and HCl gas is bubbled through it for 30 min. Sodiumsulfate (4 g) is added to the reaction mixture, which is then stirred at−10° C. overnight, warmed to 0° C. and stirred for another 5 h. Thesolids are filtered off and the filtrate is concentrated in vacuo toafford chloromethoxy-acetic acid ethyl ester as a colorless oil.

(b) (5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethoxy)-acetic acidethyl ester

A flask is charged with 5-chloro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride (Example 2) (0.930 g, 3.33 mmol) in THF (20 mL) and cooledto 0° C. KHMDS (0.5 M in toluene, 16.65 mL, 8.32 mmol) is added and themixture is stirred at room temperature for 30 min, followed by additionof chloromethoxy-acetic acid ethyl ester (1.27 g, 8.32 mmol). Thereaction mixture is stirred for 3 h, then washed with water andextracted with ethyl acetate. The organic layer is dried over sodiumsulfate and concentrated in vacuo to give a residue which is purified bysilica gel flash chromatography (dichloromethane-methanol, 19:1) toafford (5-chloro-3-methyl-2-pyridinyl-indol-1-ylmethoxy)-acetic acidethyl ester as a solid. MS (ESI) m/z 359.2 (M+H)⁺.

(c) (5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethoxy)-acetic acid

A flask is charged with(5-chloro-3-methyl-2-pyridinyl-indol-1-ylmethoxy)-acetic acid ethylester (0.622 g, 1.737 mmol) in MeOH (10 mL). Aqueous lithium hydroxide(1M, 4.34 mL, 4.34 mmol) is added and the mixture is stirred at roomtemperature for 1.5 h. The reaction mixture is acidified to pH 1 using1M aqueous HCl. The precipitate is filtered and re-crystallized in MeOHto afford (5-chloro-3-methyl-2-phenyl-indol-1-ylmethoxy)-acetic acid asa white solid. ¹H NMR (400 MHz, MeOD) δ ppm 2.27 (s, 3H), 4.02 (s, 2H),5.54 (s, 2H), 7.27 (dd, J=8.8, 2.0 Hz, 1H), 7.59-7.68 (m, 3H), 8.10(ddd, J=8.0, 1.9, 1.8 Hz, 1H), 8.67 (dd, J=4.9, 1.6 Hz, 1H), 8.74 (d,J=1.5 Hz, 1H). HRMS (ESI) m/z 331.0849 [(M+H)⁺Calcd for C₁₇H₁₆ClN₂O₃:331.0849].

Example 732-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethoxy)-ethanol

A flask is charged with(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethoxy)-acetic acid ethylester (Example 72b, 1.00 g, 2.79 mmol) and THF (10 mL). The reactionmixture is cooled to 0° C. and lithium aluminum hydride (1M in THF, 6.98mL, 6.98 mmol) is added. After stirring for 1 h at room temperature, themixture is quenched with water (0.3 mL), followed with 16% aqueous NaOH(0.3 mL). Water (1 mL) is added and stirring is continued for 10 min.The solids are filtered off and the filtrate is concentrated in vacuo.The residue is purified by silica gel flash chromatography(dichloromethane-acetonitrile, 3:1), followed by a purification onChiralcel® IA column (heptane-EtOH, 9:1) to afford2-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethoxy)-ethanol as awhite solid. ¹H NMR (400 MHz, MeOD) δ ppm 2.27 (s, 3H), 3.42-3.49 (m,2H), 3.60 (t, J=4.8 Hz, 2H), 5.47 (s, 2H), 7.27 (dd, J=8.7, 1.9 Hz, 1H),7.57-7.62 (m, 2H), 7.64 (dd, J=8.0, 4.9 Hz, 1H), 8.10 (dt, J=7.8, 1.9Hz, 1H), 8.66 (dd, J=4.9, 1.6 Hz, 1H), 8.74 (d, J=1.3 Hz, 1H). HRMS(ESI) m/z 317.1056 [(M+H)⁺Calcd for C₁₇H₁₇ClN₂O₂: 317.1507].

Example 74 (a) 3-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-propionicacid

A flask is charged with 5-chloro-3-methyl-2-pyridin-3-yl-1H-indolehydrochloride (Example 2, 0.700 g, 2.50 mmol) in DMF (7 mL) and cooledto 0° C. Potassium tert-butoxide (0.740 mg, 6.26 mmol) is added and themixture is stirred at room temperature for 30 min, then lowered backinto the ice bath. Acrylic acid methyl ester (0.680 mL, 7.52 mmol) isadded, and the reaction mixture is stirred for 1.5 h. The reactionmixture is acidified to pH 1 using 1M aqueous HCl and extracted withethyl acetate. The organic layer is dried over sodium sulfate andconcentrated in vacuo to give a residue which is purified by silica gelflash chromatography (dichloromethane-methanol, 9:1) to afford3-(5-chloro-3-methyl-2-pyridinyl-indol-1-yl)-propionic acid as a whitesolid. MS (ESI) m/z 315.18 (M+H)⁺

(b) 3-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-propan-1-ol

A flask is charged with3-(5-chloro-3-methyl-2-pyridinyl-indol-1-yl)-propionic acid (0.344 g,1.09 mmol) and THF (10 mL). The reaction mixture is cooled to 0° C. andLAH (1M in THF, 2.73 mL, 2.73 mmol) is added. After stirring at roomtemperature for 30 min, the mixture is cooled to 0° C., quenched withaqueous NaHCO₃ and extracted with ethyl acetate. The organic layer isdried over sodium sulfate and concentrated in vacuo to give a residuewhich is purified by silica gel flash chromatography(dichloromethane-methanol, 19:1) to afford3-(5-chloro-3-methyl-2-pyridinyl-indol-1-yl)-propan-1-ol as a whitesolid. ¹H NMR (400 MHz, MeOD) δ ppm 1.71-1.82 (m, 2H), 2.23 (s, 3H),3.38 (t, J=6.1 Hz, 2H), 4.18-4.24 (m, 2H), 7.21 (dd, J=8.8, 2.0 Hz, 1H),7.49 (d, J=8.6 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.65 (ddd, J=7.9, 5.0,1.0 Hz, 1H), 7.98 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.65 (dd, J=2.3, 0.8Hz, 1H), 8.67 (dd, J=5.1, 1.8 Hz, 1H). HRMS (ESI) m/z 301.1108[(M+H)⁺Calcd for C₁₇H₁₈ClN₂O: 301.1108].

Example 75 4-(5-Fluoro-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid

A flask is charged with NaH (0.284 g, 7.093 mmol) and DMSO (1.5 mL).5-Fluoro-2-pyridin-3-yl-indole (Example 7, 0.112 g, 0.507 mmol) in DMSO(0.5 mL) is added. The flask and syringes are rinsed with DMSO (2 times0.5 mL). After 10 min, ethyl 4-(bromomethyl)benzoate (0.192 g, 0.760mmol) is added neat. After 10 min, water is added. The resultingprecipitate is filtered through a sintered funnel and washed with waterand dichloromethane to give4-(5-fluoro-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid as anoff-white solid. ¹H NMR (400 MHz, MeOD) δ ppm (sodium salt) 5.49 (s,2H), 6.77 (s, 1H), 6.92 (d, J=8.1 Hz, 2H), 6.95-7.00 (m, 1H), 7.31-7.37(m, 2H), 7.49 (dd, J=7.7, 5.2 Hz, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.87-7.92(m, 1H), 8.56 (dd, J=4.9, 1.5 Hz, 1H), 8.68 (d, J=1.5 Hz, 1H). HRMS(ESI) m/z 347.1212 [(M+H)⁺Calcd for C₂₁H₁₆FN₂O₂: 347.1196].

Example 76 2,2-Dimethyl-propionic acid5-cyano-2-pyridin-3-yl-indol-1-ylmethyl ester

To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 210mg, 1.37 mmol) in THF (20 mL) at room temperature is added 0.5 M KHMDSin toluene (4.1 mL, 2.05 mmol). After 30 min, chloromethyl pivalate (510mg, 3.08 mmol) is added. The mixture is stirred under N₂ for 1 h.Saturated aqueous sodium bicarbonate (0.5 mL) is added to quench thereaction. Silica gel is added to the mixture and the solvents areremoved in vacuo. The residue is purified by silica gel flashchromatography (ethyl acetate-heptane, 0:1 to 1:0). Further purificationby HPLC using an Xbridge RP18 with a gradient of 0.1% aqueous ammoniumhydroxide in acetonitrile gives 2,2-dimethyl-propionic acid5-cyano-2-pyridin-3-yl-indol-1-ylmethyl ester as a white solid. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.20 (s, 9H), 6.08 (s, 2H), 6.77 (s, 1H), 7.49(ddd, J=7.8, 4.8, 0.8 Hz, 1H), 7.56 (dd, J=8.6, 1.8 Hz, 1H), 7.68 (d,J=8.6 Hz, 1H), 7.94 (ddd, J=7.9, 2.0 Hz, 1H), 8.01 (dd, J=1.5, 0.5 Hz,1H), 8.75 (dd, J=4.8, 1.8 Hz, 1H), 8.87 (d, J=1.5 Hz, 1H). HRMS (ESI)m/z 334.1566 [(M+H)⁺Calcd for C₂₀H₂₀N₃O₂: 334.1556].

Example 77 (a) 4,4-Dimethyl-pent-1-en-3-one

This procedure is adapted from Tetrahedron Lett. 1978, 32, 2955. A flaskis charged with 3,3-dimethyl-butan-2-one (1.00 g, 9.98 mmol),p-formaldehyde (1.34 g, 44.9 mmol), N-methylanilinium trifluoroacetate(3.31 g, 14.9 mmol) and THF (10 mL). The reaction mixture is refluxedfor 16 h, followed by addition of additional quantities ofp-formaldehyde (0.674 g, 22.45 mmol), and N-methylaniliniumtrifluoroacetate (1.64 g, 7.48 mmol). After another 5.5 h at reflux, themixture is cooled to room temperature and pentane (20 mL) is added. Abrown oil collects at the bottom of the flask. The supernatant isremoved and pentane (25 mL) is added. After decantation, the supernatantis removed. The supernatants are combined and concentrated in vacuo toafford 4,4-dimethyl-pent-1-en-3-one as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.18 (s, 9H), 5.68 (dd, J=10.4, 2.0 Hz, 1H), 6.36 (dd,J=16.9, 2.0 Hz, 1H), 6.83 (dd, J=16.9, 10.4 Hz, 1H).

(b)1-(4,4-Dimethyl-3-oxo-pentyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8,0.225 g, 1.026 mmol) in DMSO (5 mL) is added potassium tert-butoxide(0.182 g, 1.53 mmol) and the mixture is stirred at room temperature for0.5 h. 4,4-Dimethyl-pent-1-en-3-one (0.345 g, 3.078 mmol) is added andthe mixture is stirred at 50° C. overnight. Dilution with ethyl acetategives a solution which is washed with water twice, dried over sodiumsulfate and concentrated in vacuo. The residue is purified by XbridgeShield RP18 with a gradient of acetonitrile in 0.1% NH₄OH to give anoil. Addition of diethyl ether and a few drops of concentrated HCl,followed by lyophilization affords1-(4,4-dimethyl-3-oxo-pentyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile asa light yellow color solid. ¹H NMR (400 MHz, MeOD) δ ppm (HCl salt) 0.90(s, 9H), 2.94 (t, J=6.4 Hz, 2H), 4.61 (t, J=6.6 Hz, 2H), 6.88 (s, 1H),7.59 (dd, J=8.7, 1.6 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.93 (dd, J=8.0,5.4 Hz, 1H), 8.10 (d, J=1.0 Hz, 1H), 8.44 (dt, J=7.9, 1.7 Hz, 1H), 8.82(dd, J=5.3, 1.3 Hz, 1H), 8.96 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 332.1762[(M+H)⁺Calcd for C₂₁H₂₂N₃O: 332.1763].

Example 78 (a) 3,3-dimethyl-azetidin-2-one

A 250 mL Parr glass vessel is charged with Rh/Al₂O₃ (2.33 g, 1.13 mmol)and ethyl 2,2-dimethylcyanoacetate (2.0 g) dissolved in ethanol (90 mL).The flask is evacuated and filled with hydrogen (50 psi) and the mixtureis shaken under 50 psi of hydrogen. After 48 h, the mixture is filteredand concentrated in vacuo (50 Torr, 35° C., 30 min) to give a crudemixture which is dissolved in anhydrous ether (60 mL) under nitrogen andcooled to 0° C. LHMDS (1.0M in THF, 10 mL, 10 mmol) is added dropwiseand the cooling bath is removed. After 2 h, the mixture is cooled to 0°C. and quenched with 1M aqueous sodium bisulfate and diluted with ether.The organic phase is washed with 1M aqueous sodium bisulfate and brine.The pH of the combined aqueous phase is adjusted to 14 with 4M aqueoussodium hydroxide and the aqueous phase is repeatedly extracted withdichloromethane. The dichloromethane phase is dried over magnesiumsulfate, filtered and concentrated in vacuo to give a residue which ispurified by silica gel flash chromatography (ethyl acetate) to give3,3-dimethyl-azetidin-2-one as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ ppm 1.34 (s, 6H), 3.13 (s, 2H).

(b) 1-hydroxymethyl-3,3-dimethyl-azetidin-2-one

A flask is charged with 3,3-dimethyl-azetidin-2-one (0.159 g, 1.524mmol), aqueous formaldehyde (37% wt., 0.124 g, 1.524 mmol) and crushedpotassium carbonate (0.009 g, 0.061 mmol). The flask is lowered in apre-heated oil bath (75° C.). After 15 min, the flask is removed fromthe oil bath and allowed to stand at room temperature. After 2 h, themixture is taken up in acetone, dried over magnesium sulfate andfiltered through a plug of silica gel. Concentration in vacuo (30° C.,40 Torr) gives 1-hydroxymethyl-3,3-dimethyl-azetidin-2-one, which isused in the next step without further purification. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.32 (s, 6H), 3.23 (s, 2H), 4.69 (d, J=7.5 Hz, 2H).

(c)1-(3,3-dimethyl-2-oxo-azetidin-1-ylmethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile

A flask is charged with 1-hydroxymethyl-3,3-dimethyl-azetidin-2-one(0.179 g, 1.317 mmol) and dichloromethane (5 mL), and thionyl chloride(0.63 g, 5.27 mmol) is added.

The mixture is stirred at room temperature overnight and concentrated invacuo to yield an oil, which is redissolved in DMF (0.8 mL).2-Pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 0.213 g, 0.922 mmol)is dissolved in DMF (5 mL), cooled to 0° C., and NaH (0.053 g, 1.317mmol) is added portionwise. After 30 min, the chloride solution isadded. After 1 h, NaH (0.027 g, 0.67 mmol) is added and the mixture isstirred overnight. The mixture is quenched with a few drops of water anddiluted with methanol and DMSO. The mixture is purified on Xbridge C18eluting with a 9:1 to 1:9 water-acetonitrile gradient to give1-(3,3-dimethyl-2-oxo-azetidin-1-ylmethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile.¹H NMR (400 MHz, CDCl₃) δ ppm 1.18 (s, 6H), 2.82 (s, 2H), 5.47 (s, 2H),6.71 (s, 1H), 7.47-7.51 (m, 1H), 7.56 (dd, J=8.6, 1.5 Hz, 1H), 7.73 (d,J=8.6 Hz, 1H), 7.80-7.83 (m, 1H), 8.01 (d, J=1.5 Hz, 1H), 8.75-8.76 (m,2H). HRMS (ESI) m/z 331.1558 [(M+1-1)⁺Calcd for C₂₀H₁₉N₄O: 331.1559].

Example 79 5-Fluoro-3-methyl-2-pyridin-3-yl-indole-1-carboxylic acidisopropyl ester

5-Fluoro-3-methyl-2-pyridin-3-yl-indole (Example 3, 0.246 g, 1.044 mmol)is dissolved in DMF (9 mL). NaH (60%, 0.054 g, 1.357 mmol) is added andthe mixture is stirred for 1 h, whereupon isopropylchloroformate (1.0Min toluene 2.1 mL, 2.1 mmol) is added. The mixture is stirred overnight,quenched with saturated aqueous sodium bicarbonate and extracted withethyl acetate. The organic phase is dried over MgSO₄ and concentrated invacuo to give a residue, which is purified by silica gel flashchromatography (ethyl acetate-heptane, 1:4 to 2:3) to give5-fluoro-3-methyl-2-pyridin-3-yl-indole-1-carboxylic acid isopropylester as a pale yellow solid. ¹H NMR (400 MHz, MeOD) δ ppm 1.07 (d,J=6.3 Hz, 6H), 2.12 (s, 3H), 4.93-5.04 (m, 1H), 7.09-7.17 (m, 1H), 7.30(dd, J=8.8, 2.3 Hz, 1H), 7.54-7.59 (m, 1H), 7.84-7.89 (m, 1H), 8.23 (dd,J=9.1, 4.5 Hz, 1H), 8.53-8.56 (m, 1H), 8.61 (dd, J=4.5, 1.6 Hz, 1H).HRMS (ESI) m/z 313.1353 [(M+H)⁺ Calcd for C₁₈H₁₈FN₂O₂: 313.1352].

Example 80 5-Cyano-3-methyl-2-pyridin-3-yl-indole-1-carboxylic acidtert-butyl ester

To a solution of 3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile(Example 6, 96 mg, 0.40 mmol) in DMF (2 mL) at room temperature is addedtriethylamine (30 mg, 0.30 mmol), di-tert-butyl carbonate (65 mg, 0.30mmol) and 4-(N,N-dimethylamino)pyridine (2 mg, 0.020 mmol). The mixtureis stirred under N₂. The mixture is purified by Xbridge RP18 with agradient of acetonitrile in 0.1% aqueous ammonium hydroxide to give5-cyano-3-methyl-2-pyridin-3-yl-indole-1-carboxylic acid tert-butylester as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.30 (s, 9H), 2.16(s, 3H), 7.47-7.55 (m, 1H), 7.65 (dd, J=8.7, 1.6 Hz, 1H), 7.76 (d, J=7.3Hz, 1H), 7.90 (d, J=1.0 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H), 8.63 (d, J=1.8Hz, 1H), 8.69 (dd, J=5.1, 1.5 Hz, 1H). HRMS (ESI) m/z 334.1566[(M+H)⁺Calcd for C₂₀H₂₀N₃O₂: 334.1556].

Example 81 5-Cyano-2-pyridin-3-yl-indole-1-carboxylic acid tert-butylester

A mixture of 1-Boc-5-cyanoindole-2-boronic acid (339 mg, 1.19 mmol),3-bromo-pyridine (150 mg, 93 uL, 0.95 mmol), aqueous sodium carbonate(2M, 0.95 mL, 1.9 mmol) and DME (4 mL) is degassed with nitrogen andPS—Pd(PPh₃) (285 mg, 0.11 mmol/g, 0.028 mmol) is added. The resultingmixture is then heated in the microwave at 120° C. for 20 min and at130° C. for 25 min (three times). The reaction mixture is filteredthrough a sintered funnel and washed with dichloromethane (50 mL). Thefiltrate is dried over Na₂SO₄, filtered, and concentrated. The residueis purified by reverse phase HPLC (5 to 80% acetonitrile-0.1% aqueousammonia) to give 5-cyano-2-pyridin-3-yl-indole-1-carboxylic acidtert-butyl ester as a solid. ¹H NMR (400.3 MHz, CDCl₃) δ ppm 1.34 (s,9H), 6.67 (s, 1H), 7.39 (dd, J=4.9, 7.8 Hz, 1H), 7.61 (dd, J=1.6, 8.7Hz, 1H), 7.74 (m, 1H), 7.92 (s, 1H), 8.35 (d, J=8.7 Hz, 1H), 8.65 (dd,J=1.6 Hz, 4.9 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H). MS (ESI) m/z 320 (M+H)⁺.

Example 82 5-Fluoro-2-pyridin-3-yl-indole-1-carboxylic acid tert-butylester

To a solution of 5-fluoro-2-pyridin-3-yl-indole (Example 3, 0.100 g,0.452 mmol) in DMF (1 mL) is added triethylamine (0.083 g, 0.814 mmol),DMAP (0.006 g, 0.045 mmol) and di-tert-butyl carbonate (0.120 g, 0.543mmol). After 15 h, the mixture is diluted with ethyl acetate and washedwith water. The organic phase is dried over MgSO₄, filtered and thefiltrate is concentrated in vacuo to give a residue which is purified bysilica gel chromatography (heptane-ethyl acetate, 9:1 to 4:1) to give5-fluoro-2-pyridin-3-yl-indole-1-carboxylic acid tert-butyl ester as ayellow oil. Trituration with ether and heptane, followed by standing forseveral days affords a solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.35 (s,9H), 6.58 (s, 1H), 7.07-7.12 (m, 1H), 7.23 (dd, J=8.6, 2.5 Hz, 1H), 7.36(dd, J=7.8, 5.1 Hz, 1H), 7.72-7.75 (m, 1H), 8.21 (dd, J=9.1, 4.9 Hz,1H), 8.62 (dd, J=4.9, 1.5 Hz, 1H), 8.69 (d, J=1.5 Hz, 1H). MS (ESI) m/z313 (M+H)⁺.

Example 83 (a) N-(2-Cyanomethyl-phenyl)-nicotinamide

2-aminophenylacetonitrile (5.0 g, 37.1 mmol) and nicotinoyl chloride(7.5 g, 40.8 mmol) are taken up in dry dichloromethane (200 mL) anddiisopropylethylamine (12.1 g, 92.7 mmol) is added while cooling themixture with a cold water bath. The mixture is stirred overnight,whereupon it is washed twice with saturated aqueous sodium bicarbonate.The combined aqueous layer is back-extracted with ethyl acetate. Thecombined organic phase is dried over MgSO₄ and concentrated in vacuo togive a residue, which is purified by silica gel flash chromatography(dichloromethane-methanol, 1:0 to 19:1) to giveN-(2-cyanomethyl-phenyl)-nicotinamide as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 4.02 (s, 2H), 7.32-7.37 (m, 1H), 7.39-7.44 (m, 2H),7.50 (d, J=7.1 Hz, 1H), 7.59 (dd, J=8.1, 4.8 Hz, 1H), 8.30-8.33 (m, 1H),8.78 (dd, J=4.8, 1.5 Hz, 1H), 9.14 (d, J=1.8 Hz, 1H), 10.36 (s, 1H).

(b) 2-Pyridin-3-yl-1H-indole-3-carbonitrile

N-(2-cyanomethyl-phenyl)-nicotinamide (0.095 g, 0.384 mmol) is dissolvedin DMF (3 mL). NaH (60%, 0.015 g, 0.384 mmol) is added and the mixtureis heated to 130° C. After 18 h, the mixture is cooled down, dilutedwith ethyl acetate, and washed with 1M aqueous sodium hydroxide. Thecombined washings are back-extracted with ethyl acetate. The combinedorganic phase is dried over magnesium sulfate, filtered and concentratedin vacuo. The residue is purified by silica gel flash chromatography(dichloromethane-methanol, 99:1 to 19:1) to give2-pyridin-3-yl-1H-indole-3-carbonitrile as a brown solid. ¹H NMR (400MHz, MeOD) δ ppm 7.29-7.32 (m, 1H), 7.34-7.39 (m, 1H), 7.57 (d, J=8.0Hz, 1H), 7.66 (dd, J=8.0, 4.9 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 8.39-8.44(m, 1H), 8.68 (dd, J=4.8, 1.5 Hz, 1H), 9.15 (d, J=1.5 Hz, 1H).

(c) 1-Methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile

To 2-pyridin-3-yl-1H-indole-3-carbonitrile (1.0 g, 4.56 mmol) in DMF (17mL) is added 60% sodium hydride in mineral oil (547 mg, 13.68 mmol) andthe suspension is stirred for 30 min. Iodomethane (971 mg, 6.84 mmol) isthen added to the reaction mixture and stirred at ambient temperaturefor 1 h. Aqueous NaHCO₃ (3 mL) is added and the mixture is concentratedin vacuo. The residue is purified by purified by silica gel flashchromatography (dichloromethane-methanol gradient) to give1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile as a white solid. ¹HNMR (400 MHz, MeOD) δ ppm 3.83 (s, 3H), 7.35 (t, J=7.5 Hz, 1H),7.40-7.46 (m, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.67-7.74 (m, 2H), 8.16 (dt,J=8.0, 2.0, 1.9 Hz, 1H), 8.76 (dd, J=5.1, 1.5 Hz, 1H), 8.86 (d, J=1.5Hz, 1H). HRMS (ESI) m/z 234.1029 [(M+H)⁺Calcd for C₁₅H₁₂N₃: 234.1031].

Example 84 1-Ethyl-2-pyridin-3-yl-1H-indole-3-carbonitrile

To a solution of N-(2-cyanomethyl-phenyl)-nicotinamide (Example 83a, 400mg, 1.69 mmol) in DMF (17 mL) is added Cs₂CO₃ (1.1 g, 3.37 mmol). Thereaction is heated to 80° C., at which time a solution of iodoethane(0.14 mL, 1.75 mmol) in DMF (5 mL) is added over 75 min. The temperatureis then increased to 100° C. After stirring for an additional 2 h, thereaction is cooled to room temperature and quenched with saturatedaqueous NH₄Cl, and diluted with ethyl acetate and water. The layers areseparated and the aqueous layer is extracted with ethyl acetate. Thecombined organic extracts are dried over sodium sulfate, filtered, andconcentrated. The resulting residue is purified by silica gel flashchromatography (ethyl acetate-heptane, 3:10 to 1:0) to furnish1-ethyl-2-pyridin-3-yl-1H-indole-3-carbonitrile. ¹H NMR (400 MHz, CDCl₃)δ ppm 1.40 (t, J=7.2 Hz, 3H), 4.22 (q, J=7.2 Hz, 2H), 7.32-7.45 (m, 2H),7.47-7.51 (m, 1H), 7.54 (dd, J=7.8, 5.6 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H),7.91-7.98 (m, 1H), 8.78-8.85 (m, 2H). HRMS (ESI) m/z 248.1190[(M+H)⁺Calcd for C₁₆H₁₄N₃: 248.1188].

Example 85 3-(2-Ethoxy-ethyl)-1-ethyl-2-pyridin-3-yl-1H-indole

To a solution of 1-ethyl-2-pyridin-3-yl-1H-indole-3-carbonitrile(Example 84, 590 mg, 2.4 mmol) in toluene (20 mL) at −60° C. is added a1 M solution of DIBAL-H (3.6 mL, 3.6 mmol). The reaction is stirred for1 h and kept below −40° C. The reaction is then quenched with water (1mL) and brought to room temperature. Anhydrous sodium sulfate (ca. 2 g)is then added to the reaction mixture. The reaction mixture is filteredthrough a plug of celite. Sulfuric acid (2M, ca. 5 mL) is added and uponcomplete conversion to the desired aldehyde, the reaction mixture isbrought to pH 8 with the addition of Na₂CO₃, and extracted with ethylacetate. The organic extract is washed with brine, dried over Na₂SO₄,filtered, and concentrated. The resulting1-ethyl-2-pyridin-3-yl-1H-indole-3-carbaldehyde is used without furtherpurification. To a solution of ethoxymethyltriphenylphosphonium chloride(0.32 g, 0.9 mmol) in THF (3 mL) is added potassium tert-butoxide (1 Min THF, 0.93 mL, 0.93 mmol). The resulting red solution is permitted tostir for 15 min, at which time a solution of1-ethyl-2-pyridin-3-yl-1H-indole-3-carbaldehyde (75 mg, 0.3 mmol) in THF(3 mL) is added. The reaction is stirred for 1 h, quenched withsaturated aqueous NH₄Cl, diluted with water and extracted with ethylacetate. The organic extract is dried over Na₂SO₄, filtered, andconcentrated. The resulting E/Z mixture of3-(2-ethoxy-vinyl)-1-ethyl-2-pyridin-3-yl-1H-indole is then dissolved inmethanol (5 mL) and 10% Pd/C (32 mg, 0.03 mmol) is added. The reactionmixture is stirred under an atmosphere of H₂ gas (balloon) for 2 h. Thereaction is then filtered through a plug of celite and concentrated todryness. The resulting residue is purified by silica gel flashchromatography (ethyl acetate-heptane, 0:1 to 2:5) to afford3-(2-ethoxy-ethyl)-1-ethyl-2-pyridin-3-yl-1H-indole. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.17 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H), 2.94 (t,J=7.3 Hz, 2H), 3.43 (q, J=7.1 Hz, 2H), 3.61 (t, J=7.3 Hz, 2H), 4.05 (q,J=7.3 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 7.30 (t, J=7.1 Hz, 1H), 7.40 (d,J=8.3 Hz, 1H), 7.53 (dd, J=7.6, 5.1 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H),7.92 (d, J=7.8 Hz, 1H), 8.72 (dd, J=4.9, 1.6 Hz, 1H), 8.77 (d, J=1.5 Hz,1H). HRMS (ESI) m/z 295.1805 [(M+H)⁺Calcd for C₁₉H₂₃N₂O: 295.1810].

Example 86 (a) 4-Chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine

To a mixture of 3-ethynylpyridine (1.13 g, 11 mmol) and2-fluoro-4-chloro-6-iodoaniline (2.71 g, 10 mmol) in triethylamine (100mL) is added PdCl₂(PPh₃)₂ (175 mg, 0.25 mmol) and CuI (95 mg, 0.50 mmol)and the mixture is refluxed for 1 h. The solvent is removed in vacuo andthe residue is purified by silica gel flash chromatography(dichloromethane-methanol, 1:0 to 24:1) to give4-chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine. MS (ESI) m/z 247(M+H)⁺.

(b) 5-Chloro-7-fluoro-2-pyridin-3-yl-1H-indole

To a solution of 4-chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine(3.1 g, 12.57 mmol) in NMP (40 mL) is added potassium tert-butoxide (2.1g, 18.85 mmol) and the mixture is stirred overnight. Water (1 mL) isadded to quench the reaction and the mixture is poured into water (100mL). The mixture is extracted with diethyl ether five times. Thecombined organic phase is partially concentrated, resulting inprecipitation of the product, which is filtered through a glass sinteredfunnel and washed with dichloromethane to afford5-chloro-7-fluoro-2-pyridin-3-yl-1H-indole as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.10-7.15 (m, 2H), 7.47-7.53 (m, 2H), 8.31 (dt,J=8.2, 1.9, 1.8 Hz, 1H), 8.55 (d, J=4.3 Hz, 1H), 9.16 (s, 1H), 12.23 (s,1H).

Example 87 5-Chloro-2-pyridin-3-yl-1H-indole

3-Ethynylpyridine and 4-chloro-6-iodoaniline are processed according tothe method described in Example 86 to give5-chloro-2-pyridin-3-yl-1H-indole. ¹H NMR (400 MHz, MeOD) δ ppm 6.96 (s,1H), 7.14 (dd, J=8.6, 2.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.54 (dd,J=8.0, 4.9 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 8.25 (dt, J=8.0, 1.9 Hz,1H), 8.50 (d, J=4.5 Hz, 1H), 9.02 (s, 1H). HRMS (ESI) m/z 229.0522[(M+H)⁺Calcd for C₁₃H₁₀ClN₂: 229.0533].

Example 88 5,6-Dimethyl-2-pyridin-3-yl-1H-indole

3-Ethynylpyridine and 3,4-dimethyl-6-iodoaniline are processed accordingto the method described in Example 86 to give5,6-dimethyl-2-pyridin-3-yl-1H-indole. MS (ESI) m/z 223.13 (M+H)⁺.

Example 89 6-Fluoro-2-pyridin-3-yl-1H-indole

3-Ethynylpyridine and 3-fluoro-6-iodoaniline are processed according tothe method described in Example 86 to give6-fluoro-2-pyridin-3-yl-1H-indole. MS (ESI) m/z 213.0 (M+H)⁺.

Example 90 (a) 4-Methoxy-pyridine-3-carbaldehyde

A flask is charged with 1.7M tert-butyllithium in pentane (47.1 mL, 80.1mmol) and THF (20 mL), and cooled to −78° C. 2-Bromomesitylene (6.0 mL,39 mmol) is added dropwise. The mixture is stirred for 1 h, and4-methoxypyridine (3.0 mL, 30 mmol) is added dropwise. The mixture iswarmed to −23° C. and stirred for 3 h. The mixture is cooled again to−78° C. and dimethylformamide (3.5 mL, 45 mmol) is added. After 1 h,brine (50 mL) is added to the mixture at −78° C. and warmed to roomtemperature. The mixture is extracted with ether and the combinedorganic layer is dried over Na₂SO₄. Concentration followed by silica gelchromatography eluting with a 0 to 6% methanol-dichloromethane gradientgives 4-methoxy-pyridine-3-carbaldehyde. ¹H NMR (400 MHz, CDCl₃) δ ppm4.01 (s, 3H), 6.94 (d, J=5.8 Hz, 1H), 8.65 (d, J=5.8 Hz, 1H), 8.90 (s,1H), 10.46 (s, 1H).

(b) 3-(2,2-dibromo-vinyl)-4-methoxy-pyridine

A flask is charged with triphenylphosphine (21.4 g, 81.6 mmol), carbontetrabromide (13.5 g, 40.8 mmol) and dichloromethane (300 mL).4-Methoxy-pyridine-3-carbaldehyde (2.8 g, 20.4 mmol) in dichloromethane(300 mL) is added at 0° C. The mixture is stirred at 0° C. for 1 h. Themixture is extracted with saturated aqueous ammonium chloride and theaqueous phase is neutralized with NaHCO₃ and extracted withdichloromethane. The organic phase is dried over Na₂SO₄, concentratedand purified by silica gel chromatography eluting with a 0 to 10%methanol-dichloromethane gradient to give3-(2,2-dibromo-vinyl)-4-methoxy-pyridine. ¹H NMR (400 MHz, CDCl₃) δ ppm3.90 (s, 3H), 6.81 (d, J=5.8 Hz, 1H), 7.48 (s, 1H), 8.48 (d, J=5.8 Hz,1H), 8.76 (s, 1H).

(c) 4-methoxy-3-ethynyl-pyridine

A flask is charged with 3-(2,2-dibromo-vinyl)-4-methoxy-pyridine (3.7 g,12.63 mmol) and THF (100 mL), and 1.6 M nBuLi in pentane (17.4 mL, 27.79mmol) is added dropwise at −78° C. The mixture is stirred at −78° C. for1 h before addition of saturated aqueous NH₄Cl (0.5 mL). The mixture iswarmed to room temperature and poured into water (100 mL). The mixtureis extracted with ethyl acetate and the combined organic phase is driedover Na₂SO₄. Concentration followed by silica gel flash chromatographyeluting with a 0 to 5% methanol-dichloromethane gradient gives4-methoxy-3-ethynyl-pyridine. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.39 (s,1H), 3.96 (s, 3H), 6.82 (d, J=5.8 Hz, 1H), 8.46 (d, J=5.8 Hz, 1H), 8.58(s, 1H).

(d) 2-(4-Methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile

4-Methoxy-3-ethynyl-pyridine and 4-cyano-6-iodoaniline are processedaccording to the method described in Example 86 to give2-(4-methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile.2-(4-Methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile is purified by HPLCusing an Xbridge Shield RP18 with a gradient of acetonitrile in 0.1%NH₄OH. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.04 (s, 3H), 7.14 (d, J=1.3 Hz,1H), 7.25 (d, J=5.8 Hz, 1H), 7.47 (dd, J=8.5, 1.6 Hz, 1H), 7.61 (d,J=8.3 Hz, 1H), 8.11 (s, 1H), 8.47 (d, J=5.8 Hz, 1H), 8.91 (s, 1H), 11.91(br. s., 1H). HRMS (ESI) m/z 250.0968 [(M+H)⁺ calcd for C₁₆H₁₂N₃O:250.0980].

Example 91 2-(5-Chloro-pyridin-3-yl)-1H-indole

A flask is charged with N-Boc-indole-2-boronic acid (0.407 g, 1.55mmol), 3-chloro-5-bromopyridine (0.200 g, 1.03 mmol), s-phos (0.021 g,0.05 mmol), potassium phosphate (0.441 g, 2.07 mmol) and toluene (5 mL).The flask is evacuated and filled with N₂ thrice and Pd₂(dba)₃ (0.019 g,0.02 mmol) is added. The flask is evacuated and filled with N₂ thrice.The mixture is refluxed for 1 h, then cooled to room temperature andfiltered through celite. The filtrate is concentrated in vacuo to afford2-(5-chloro-pyridin-3-yl) -indole-1-carboxylic acid tert-butyl ester asan oil. The residue is dissolved in DCM (5 mL) and trifluoroacetic acid(2 mL) is added. The reaction mixture is stirred at room temperature for4 h, followed with quenching with a saturated sodium bicarbonatesolution. Extraction with dichloromethane, drying of the organic layerover sodium sulfate and concentration in vacuo gives a residue which ispurified by silica gel flash chromatography (heptane-ethyl acetate, 3:2)to afford 2-(5-chloro-pyridin-3-yl)-1H-indole. ¹H NMR (400 MHz, MeOD) δppm 7.06 (s, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H), 7.45(d, J=8.3 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 8.30 (t, J=2.1 Hz, 1H), 8.47(d, J=2.3 Hz, 1H), 8.96 (d, J=1.8 Hz, 2H). HRMS (ESI) m/z 229.0542[(M+H)+calcd for C₁₃H₁₀ClN₂: 229.0533].

Example 92 2-(5-Fluoro-pyridin-3-yl)-1H-indole

3-Fluoro-5-bromopyridine is processed according to the proceduredescribed in Example 91 to give 2-(5-fluoro-pyridin-3-yl)-1H-indole.HRMS (ESI) m/z 213.0834 [(M+H)⁺Calcd for C₁₃H₁₀N₂F: 213.0828].

Example 93 5-Methoxy-2-pyridin-3-yl-1H-indole

3-Bromopyridine and N-Boc-5-methoxy-indole-2-boronic acid are processedaccording to the procedure described in Example 91 to give5-methoxy-2-pyridin-3-yl-1H-indole. HRMS (ESI) m/z 225.1026 [(M+H)⁺Calcdfor C₁₄H₁₃N₂O: 225.1028]

Example 94 6-Chloro-2-(5-methyl-pyridin-3-yl)-1H-indole

3-Methyl-5-bromopyridine and N-Boc-6-chloro-indole-2-boronic acid areprocessed according to the procedure described in Example 91 to give6-chloro-2-(5-methyl-pyridin-3-yl)-1H-indole. (ESI) m/z 243.0 (M+H)⁺.

Example 95 6-Chloro-2-(5-trifluoromethyl-pyridin-3-yl)-1H-indole

3-Trifluoromethyl-5-bromopyridine and N-Boc-6-chloro-indole-2-boronicacid are processed according to the procedure described in Example 91 togive 6-chloro-2-(5-trifluoromethyl-pyridin-3-yl)-1H-indole. (ESI) m/z297.0 (M+H)⁺.

Example 96 5-Fluoro-2-(5-fluoro-pyridin-3-yl)-1H-indole

3-Fluoro-5-bromopyridine and N-Boc-5-fluoro-indole-2-boronic acid areprocessed according to the procedure described in Example 91 to give5-fluoro-2-(5-fluoro-pyridin-3-yl)-1H-indole. (ESI) m/z 231.04 (M+H)⁺.

Example 97 6-Chloro-2-pyridin-3-yl-1H-indole

3-Bromopyridine and N-Boc-6-chloro-indole-2-boronic acid are processedaccording to the procedure described in Example 91 to give6-chloro-2-pyridin-3-yl-1H-indole. (ESI) m/z 229.0 (M+H)⁺.

Example 98 2-(5-Benzyloxy-pyridin-3-yl)-6-chloro-1H-indole

A flask is charged with 6-chloro-1-Boc-indole-2-boronic acid (0.839 g,2.83 mmol), 1-benzyloxy-3-bromo-pyridine (0.500 g, 1.89 mmol), potassiumphosphate (1.2 g, 5.67 mmol) and DMF (5 mL). The flask is evacuated andfilled with nitrogen thrice and Pd(PPh₃)₄ (0.164 g, 0.141 mmol) isadded. The flask is evacuated and filled with nitrogen thrice again, andheated to 80° C. for 3.5 h. The mixture is then diluted with ethylacetate and washed with water thrice. The organic layer is dried oversodium sulfate and concentrated in vacuo. The residue is redissolved inDCM (1 mL) and trifluoroacetic acid (2 mL) is added. After 1 h, 4Maqueous NaOH is added and following extraction with DCM, the organiclayer is dried over sodium sulfate and concentrated in vacuo. Theresidue is purified by silica gel flash chromatography (heptane-ethylacetate, 1:1) to afford 2-(3-benzyloxy-phenyl)-6-chloro-1H-indole as ayellow solid. MS (ESI) m/z 335.07 (M+H)⁺.

Example 99 2-(5-Ethoxy-pyridin-3-yl)-6-chloro-1H-indole

1-Ethoxy-3-bromo-pyridine is processed according to the method describedin Example 98 to give 2-(5-ethoxy-pyridin-3-yl)-6-chloro-1H-indole. MS(ESI) m/z 273.27 (M−H)⁺

Example 100 2-(5-Amino-pyridin-3-yl)-1-methyl-1H-indole

A flask is charged with 3-amino-5-bromopyridine (0.173 g, 0.950 mmol),N-methyl-indole boronic acid (0.262 g, 1.425 mmol), s-Phos (0.030 g,0.071 mmol), finely crushed potassium phosphate (0.407 g, 1.900 mmol)and toluene (4 mL). After degassing for 30 min, Pd₂ dba₃ (0.018 g, 0.019mmol) is added, the flask is flushed with nitrogen and the mixture isheated to 85° C. After 3 h, the mixture is allowed to cool to r.t.,diluted with ethyl acetate and filtered through a plug of silica gel(elution with ethyl acetate). The residue is purified by silica gelflash chromatography (heptane-ethyl acetate, 3:7 to 0:1) to give2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole as an off-white powder. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.74 (s, 3H), 5.49 (s, 2H), 6.56 (s, 1H),7.05-7.09 (m, 1H), 7.09-7.10 (m, 1H), 7.17-7.21 (m, 1H), 7.49 (d, J=7.6Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.99 (d, J=2.5Hz, 1H). MS (ESI) m/z 224 (M+H)⁺.

Example 101 2-(5-Methoxy-pyridin-3-yl)-1-methyl-1H-indole

5-Methoxy-3-bromo-pyridine is processed according to the methoddescribed in Example 100 to give2-(5-methoxy-pyridin-3-yl)-1-methyl-1H-indole. ¹H NMR (400 MHz, MeOD) δppm 3.82 (s, 3H), 4.00 (s, 3H), 6.69 (d, J=0.8 Hz, 1H), 7.08-7.16 (m,1H), 7.23-7.30 (m, 1H), 7.47 (dd, J=8.3, 0.8 Hz, 1H), 7.58-7.66 (m, 2H),8.32 (d, J=2.8 Hz, 1H), 8.37 (d, J=1.6 Hz, 1H). HRMS (ESI) m/z 239.1175[(M+H)⁺Calcd for C₁₅H₁₆N₂O: 239.1184].

Example 102 5-(1-Methyl-1H-indol-2-yl)-nicotinic acid ethyl ester

5-Bromo-nicotinic acid ethyl ester is processed according to the methoddescribed in Example 100 to give 5-(1-methyl-1H-indol-2-yl)-nicotinicacid ethyl ester. ¹H NMR (400 MHz, MeOD) δ ppm 1.47 (t, J=7.1 Hz, 3H),3.83 (s, 3H), 4.50 (q, J=7.1 Hz, 2H), 6.76 (s, 1H), 7.14 (t, J=7.5 Hz,1H), 7.29 (t, J=7.6 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.64 (d, J=8.1 Hz,1H), 8.56 (t, J=2.0 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H), 9.17 (d, J=2.0 Hz,1H). HRMS (ESI) m/z 281.1297 [(M+H)⁺Calcd for C₁₇H₁₇N₂O₂: 281.1290].

Example 103 5-(1H-Indol-2-yl)-pyridine-3-carbaldehyde

A flask is charged with 3-bromopyridine-5-carboxaldehyde (4.12 g, 21.48mmol), N-Boc-indoleboronic acid (8.59 g, 32.23 mmol), s-Phos (0.68 g,1.61 mmol), finely crushed potassium phosphate (9.21 g, 42.97 mmol) andtoluene (70 mL). After degassing for 1 h, Pd₂ dba₃ (0.40 g, 0.43 mmol)is added, the flask is flushed with nitrogen and the mixture is heatedto 85° C. After 30 min, the mixture is allowed to cool to r.t., dilutedwith ethyl acetate and filtered through a plug of silica gel. Silica gel(50 g) is added to the filtrate and the mixture is concentrated invacuo. The residue is heated to 60° C. with gentle stirring under oilpump vacuum overnight. The mixture is then loaded on a silica gel flashchromatography column and eluted (heptane-ethyl acetate, 4:1 to 2:3) togive 5-(1H-indol-2-yl)-pyridine-3-carbaldehyde. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.02-7.08 (m, 1H), 7.14-7.19 (m, 1H), 7.20 (d, J=1.5 Hz,1H), 7.45 (d, J=8.1 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 8.66 (t, J=2.1 Hz,1H), 9.00 (d, J=1.8 Hz, 1H), 9.39 (d, J=2.3 Hz, 1H), 10.18 (s, 1H),11.86 (br. s., 1H). MS (ESI) m/z 223.02 (M+H)⁺.

Example 104 5-(6-Chloro-1H-indol-2-yl)-pyridine-3-carbaldehyde

A flask is charged withN-(tent-butoxycarbonyl)-6-chloro-1H-indol-2-ylboronic acid (8.3 g, 28.1mmol), 5-bromonicotinaldehyde (4.35 g, 23.4 mmol), K₃PO₄ (9.94 g, 46.8mmol), s-Phos (0.480 g, 1.170 mmol) and Pd₂(dba)₃ (0.429 g, 0.468 mmol),and the flask is flushed with N₂. Toluene (250 mL) is added, and themixture is heated to 85° C. for 1.5 h. The mixture is cooled to roomtemperature. Ethyl acetate (250 mL) is added and the mixture is filteredthrough a pad of silica gel, which is washed with EtOAc. Silica gel isadded to the combined filtrate, which is concentrated in vacuo. Theresidue is placed under high vacuum at 63° C. overnight, and afterelution with ethyl acetate,5-(6-chloro-1H-indol-2-yl)-pyridine-3-carbaldehyde is obtained. MS (ESI)m/z 257.0 and 258.9 (M+H)⁺.

Example 105 (a) 3-Bromo-5-vinyl-pyridine

To a solution of methyltriphenylphosphine bromide (3.16 g, 8.87 mmol) intetrahydrofuran (20 mL) is added sodium hexamethyldisilazane (1Msolution in THF, 9.67 mL, 9.67 mmol) dropwise. The reaction mixture isstirred at room temperature for 30 min, whereupon5-bromo-pyridine-3-carbaldehyde (1.5 g, 8.06 mmol) is added. Thereaction mixture is allowed to stir at room temperature for 1 h. Themixture is concentrated and the residue is purified by silica gel flashchromatography (heptane-ethyl acetate, 7:3) to afford3-bromo-5-vinyl-pyridine as a colorless oil. MS (ESI) m/z 185.91 (M+H)⁺.

(b) 1-Methyl-2-(5-vinyl-pyridin-3-yl)-1H-indole

3-Bromo-5-vinyl-pyridine is processed according to the method describedin Example 100 to give 1-methyl-2-(5-vinyl-pyridin-3-yl)-1H-indole. MS(ESI) m/z 235.40 (M+H)⁺.

Example 106 (a) (3-Bromo-pyridin-4-yl)-methanol

To a solution of 3-bromo-pyridine-4-carbaldehyde (0.500 g, 2.68 mmol) inMeOH (5 mL) at 0° C. is added sodium borohydride (0.122 g, 3.22 mmol).The mixture is stirred at room temperature for 1 h followed by removalof the solvent in vacuo. The residue is redissolved in DCM and washedwith water twice. The organic layer is dried over sodium sulfate andconcentrated in vacuo to afford (3-bromo-pyridin-4-yl)-methanol as ayellow oil. MS (ESI) m/z 189.9 (M+H)⁺

(b) [3-(1-Methyl-1H-indol-2-yl)-pyridin-4-yl]-methanol

A microwave reactor is charged with 1-methyl-indole-2-boronic acid (1.18g, 6.78 mmol), (3-bromo-pyridin-4-yl)-methanol (0.850 g, 4.52 mmol),potassium phosphate (1.91 g, 9.04 mmol) and DMF (10 mL). The reactor isevacuated and filled with nitrogen thrice and Pd(PPh₃)₄ (0.261 g, 0.226mmol) is added. The reactor is evacuated and filled with nitrogen thriceagain. The mixture is heated to 120° C. for 1 h under microwaveirradiation, then diluted with ethyl acetate and washed with waterthrice. The organic layer is dried over sodium sulfate and concentratedin vacuo to give a residue which is purified by silica gel flashchromatography (dichloromethane-methanol, 19:1) to afford[3-(1-methyl-1H-indol-2-yl)-pyridin-4-yl]-methanol as a white solid. ¹HNMR (400 MHz, MeOD) δ ppm 3.58 (s, 3H), 4.57 (s, 2H), 6.54 (s, 1H), 7.14(t, J=7.5 Hz, 1H), 7.27 (ddd, J=7.6, 1.1 Hz, 1H), 7.46 (d, J=8.3 Hz,1H), 7.62 (d, J=7.8 Hz, 1H), 7.81 (d, J=5.1 Hz, 1H), 8.49 (s, 1H), 8.67(d, J=5.1 Hz, 1H). HRMS (ESI) m/z 239.1177 [(M+H)⁺Calcd for C₁₅H₁₅N₂O:239.1184].

Example 107 2-(4-Chloro-pyridin-3-yl)-1-methyl-1H-indole

3-Bromo-4-chloropyridine is processed according to the method describedin Example 106b to give 2-(4-chloro-pyridin-3-yl)-1-methyl-1H-indole. ¹HNMR (400 MHz, MeOD) δ ppm 3.64 (s, 3H), 6.61 (s, 1H), 7.14 (t, J=7.5 Hz,1H), 7.28 (t, J=7.6 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.64 (d, J=7.8 Hz,1H), 7.73 (d, J=5.3 Hz, 1H), 8.62 (d, J=5.6 Hz, 1H), 8.66 (s, 1H). HRMS(ESI) m/z 243.0686 [(M+H)⁺Calcd for C₁₄H₁₂ClN₂: 243.0689].

Example 108 2-(5-Hydroxy-pyridin-3-yl)-1-methyl-1H-indole

3-Bromo-5-hydroxypyridine is processed according to the method describedin Example 106b to give 2-(5-hydroxy-pyridin-3-yl)-1-methyl-1H-indole.HRMS (ESI) m/z 225.1028 [(M+H)⁺Calcd for C₁₄H₁₃N₂O: 225.1028].

Example 109 2-(5-Benzyloxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole

A flask is charged with 2-(5-benzyloxy-pyridin-3-yl)-6-chloro-1H-indole(Example 98, 0.435 g, 1.29 mmol), dimethyl carbonate (0.328 mL, 3.89mmol), potassium carbonate (0.098 g, 0.714 mmol) and DMF (3 mL). Thereaction mixture is stirred at 150° C. overnight. It is then cooled toroom temperature, diluted with ethyl acetate and washed with water. Theorganic layer is dried over sodium sulfate and concentrated in vacuo, togive a residue which is purified by flash chromatography (heptane-ethylacetate, 1:1) to afford2-(5-benzyloxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole as a solid. ¹HNMR (400 MHz, MeOD) δ ppm 3.70 (s, 3H), 5.31 (s, 2H), 6.67 (d, J=0.8 Hz,1H), 7.10 (dd, J=8.3, 1.8 Hz, 1H), 7.35-7.40 (m, 1H), 7.41-7.47 (m, 2H),7.49-7.55 (m, 3H), 7.57 (d, J=8.3 Hz, 1H), 7.64 (dd, J=2.5, 1.8 Hz, 1H),8.35 (d, J=1.8 Hz, 1H), 8.39 (d, J=2.8 Hz, 1H); HRMS (ESI) m/z 349.1108[(M+H)⁺Calcd for C₂₁H₁₈ClN₂O: 349.1108].

Example 110 2-(5-Ethoxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole

2-(5-Ethoxy-pyridin-3-yl)-6-chloro-1H-indole (Example 99) is processedaccording to the method described in Example 109 to give2-(5-ethoxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole. MS (ESI) m/z287.07 (M+H)⁺.

Example 111 6-Chloro-2-(5-methyl-pyridin-3-yl)-1-methyl-1H-indole

6-Chloro-2-(5-methyl-pyridin-3-yl)-1H-indole (Example 94) is processedaccording to the method described in Example 109 to give6-chloro-2-(5-methyl-pyridin-3-yl)-1-methyl-1H-indole. MS (ESI) m/z257.1 (M+H)⁺.

Example 1126-Chloro-2-(5-trifluoromethyl-pyridin-3-yl)-1-methyl-1H-indole

6-Chloro-2-(5-trifluoromethyl-pyridin-3-yl)-1H-indole (Example 95) isprocessed according to the method described in Example 109 to give6-chloro-2-(5-trifluoromethyl-pyridin-3-yl)-1-methyl-1H-indole. MS (ESI)m/z 311.0 (M+H)⁺.

Example 113 6-Chloro-2-pyridin-3-yl-1-methyl-1H-indole

6-Chloro-2-pyridin-3-yl-1H-indole (Example 97) is processed according tothe method described in Example 109 to give6-chloro-2-pyridin-3-yl-1-methyl-1H-indole. MS (ESI) m/z 243.02 (M+H)⁺.

Example 114 2-(4-Methoxy-pyridin-3-yl)-1-methyl-1H-indole-5-carbonitrile

To a solution of 2-(4-methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile(Example 90, 178 mg, 0.649 mmol) in DMF (4 mL) is added 60% sodiumhydride in mineral oil (78 mg, 1.95 mmol) and the suspension is stirredfor 30 min. Iodomethane (138 mg, 0.97 mmol) is then added to thereaction mixture which is stirred at ambient temperature for 1 h.Aqueous NaHCO₃ (3 mL) is added to quench the reaction and the mixture isfiltered and purified by HPLC using an Xbridge C18 with a gradient ofacetonitrile in 0.1% NH₄OH to afford2-(4-methoxy-pyridin-3-yl)-1-methyl-1H-indole-5-carbonitrile as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.59 (s, 3H), 3.89 (s, 3H), 6.67(s, 1H), 7.27 (d, J=5.8 Hz, 1H), 7.54 (dd, J=8.6, 1.5 Hz, 1H), 7.70 (d,J=8.6 Hz, 1H), 8.11 (d, J=1.1 Hz, 1H), 8.42 (s, 1H), 8.60 (d, J=5.8 Hz,1H). HRMS (ESI) m/z 264.1138 [(M+H)⁺ calcd for C₁₆H₁₄N₃O: 264.1137].

Example 115 2-(5-Chloro-pyridin-3-yl)-1-methyl-1H-indole

2-(5-Chloro-pyridin-3-yl)-1H-indole (Example 91) is processed accordingto the method described in Example 114 to give2-(5-chloro-pyridin-3-yl)-1-methyl-1H-indole. ¹H NMR (400 MHz, MeOD) δppm 3.83 (s, 3H), 6.74 (s, 1H), 7.14 (t, J=7.5 Hz, 1H), 7.25-7.33 (m,1H), 7.49 (d, J=8.3 Hz, 1H), 7.64 (dd, J=7.8, 0.6 Hz, 1H), 8.14 (t,J=2.7 Hz, 1H), 8.63 (dd, J=2.2, 0.9 Hz, 1H), 8.74 (d, J=1.3 Hz, 1H).HRMS (ESI) m/z 243.0686 [(M+H)⁺Calcd for C₁₄H₁₂ClN₂: 243.0689].

Example 116 5-Methoxy-1-methyl-2-pyridin-3-yl-1H-indole

5-Methoxy-2-pyridin-3-yl-1H-indole (Example 93) is processed accordingto the procedure described in Example 114 to give5-methoxy-1-methyl-2-pyridin-3-yl-1H-indole. ¹H NMR (400 MHz, MeOD) δppm 3.78 (s, 3H), 3.87 (s, 3H), 6.61 (d, J=0.8 Hz, 1H), 6.93 (dd, J=8.9,2.5 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.60 (ddd,J=8.0, 4.9, 0.9 Hz, 1H), 8.06 (dt, J=7.9, 2.2, 1.6 Hz, 1H). HRMS (ESI)m/z 239.1181 [(M+H)⁺ Calcd for C₁₅H₁₅N₂O: 239.1184].

Example 117 2-(5-Fluoro-pyridin-3-yl)-1-methyl-1H-indole

2-(5-Fluoro-pyridin-3-yl)-1H-indole (Example 92) is processed accordingto the procedure described in Example 114 to give2-(5-fluoro-pyridin-3-yl)-1-methyl-1H-indole. ¹H NMR (400 MHz, MeOD) δppm 3.83 (s, 3H), 6.74 (s, 1H), 7.10-7.17 (m, 1H), 7.26-7.32 (m, 1H),7.48 (d, J=8.3 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.91 (ddd, J=9.6, 2.8,1.8 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.67 (t, J=1.5 Hz, 1H). HRMS (ESI)m/z 227.0989 [(M+H)⁺Calcd for C₁₄H₁₂FN₂: 227.0985].

Example 118 5-Fluoro-2-(5-fluoro-pyridin-3-yl)-1-methyl-1H-indole

5-Fluoro-2-(5-fluoro-pyridin-3-yl)-1H-indole (Example 96) is processedaccording to the procedure described in Example 114 to give5-fluoro-2-(5-fluoro-pyridin-3-yl)-1-methyl-1H-indole. (ESI) m/z 245.34(M+H)⁺.

Example 119 1,3-Dimethyl-2-(pyridin-3-yl)-1H-indole

3-Methyl-2-(pyridin-3-yl)-1H-indole hydrochloride (Example 1) isprocessed according to the procedure described in Example 114 to give1,3-dimethyl-2-(pyridin-3-yl)-1H-indole. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.23 (s, 3H), 3.62 (s, 3H), 7.06-7.12 (m, 1H), 7.22 (td, J=7.6, 1.1 Hz,1H), 7.48 (d, J=8.3 Hz, 1H), 7.55-7.61 (m, 2H), 7.93 (dt, J=7.9, 2.0 Hz,1H), 8.66 (dd, J=4.8, 1.5 Hz, 1H), 8.69 (dd, J=2.3, 0.8 Hz, 1H). HRMS:(ESI) m/z 223.1236 [(M+H)⁺ Calcd for C₁₆H₁₆N₂: 223.1230].

Example 120 5-(6-Chloro-1-methyl-1H-indol-2-yl)-nicotinonitrile

3-Bromo-5-cyano-pyridine and N-Boc-6-chloro-indoleboronic acid areprocessed according to the procedure described in Example 103 to give5-(6-chloro-1H-indol-2-yl)-nicotinonitrile, which is processed accordingto the procedure described in Example 114 to give5-(6-Chloro-1-methyl-1H-indol-2-yl)-nicotinonitrile. ¹H NMR (400 MHz,MeOD) δ ppm 3.81 (s, 3H), 6.81 (s, 1H), 7.14 (dd, J=8.6, 1.8 Hz, 1H),7.56 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 8.46 (t, J=2.1 Hz, 1H), 8.98 (d,J=2.0 Hz, 1H), 9.06 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 268.0636[(M+H)⁺Calcd for C₁₆H₁₀ClN₃ 268.0636].

Example 121 (a) 2-(5-bromopyridin-3-yl)-1H-indole

A flask containing 1-(tert-butoxycarbonyl)-1H-indol-2-ylboronic acid (2g, 7.66 mmol), 3-bromo-5-iodopyridine (1.45 g, 5.11 mmol), 2M K₂CO₃ inwater (5.11 mL, 10.21 mmol), PS—Pd(PPh₃)₄ (2.84 g, 0.255 mmol) isflushed with N₂ and dioxane (50 mL) is added. The mixture is stirred at60° C. for 3 h, whereupon another portion of 3-bromo-5-iodopyridine (300mg, 1.06 mmol) is added. The mixture is stirred at 60° C. overnight. Themixture is cooled to room temperature and silica gel (20 g) is added.The suspension is concentrated in vacuo and the residue is placed underhigh vacuum at 60° C. over the weekend. The mixture is purified bysilica chromatography eluting with a 1:9 to 7:3 EtOAc-heptane gradientto give 2-(5-bromopyridin-3-yl)-1H-indole. MS (ESI) m/z 273.0, 275.1(M+H)⁺.

(b) 2-(5-Bromopyridin-3-yl)-3-(trifluoromethyl)-1H-indole

A flask is charged with 2-(5-bromopyridin-3-yl)-1H-indole (1.2 g, 4.39mmol), acetonitrile (100 mL), potassium carbonate (1.2 g, 8.79 mmol) and5-(trifluoromethyl)-5H-dibenzo[b,d]thiophenium trifluoromethanesulfonate(2.65 g, 6.59 mmol). The flask is lowered into an oil bath preheated to70° C., and the mixture is stirred under N₂ overnight. The mixture iscooled to room temperature and silica gel (10 g) is added. Thesuspension is concentrated in vacuo and the residue is purified bysilica chromatography eluting with a 0 to 30% EtOAc-heptane gradient togive 2-(5-bromopyridin-3-yl)-3-(trifluoromethyl)-1H-indole; ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.25 (t, J=7.6 Hz, 1H), 7.33 (t, J=7.1 Hz, 1H), 7.55(d, J=8.1 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 8.33 (t, J=2.0 Hz, 1H), 8.79(d, J=1.8 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H).

(c) 2-(5-Bromopyridin-3-yl)-1-methyl-3-(trifluoromethyl)-1H-indole

2-(5-Bromopyridin-3-yl)-3-(trifluoromethyl)-1H-indole is processedaccording to the method described in Example 114 to give2-(5-bromopyridin-3-yl)-1-methyl-3-(trifluoromethyl)-1H-indole. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 3.62 (s, 3H), 7.30 (t, J=8.0 Hz, 1H), 7.37-7.44(m, 1H), 7.71 (d, J=8.8 Hz, 2H), 8.36 (t, J=2.0 Hz, 1H), 8.72 (d, J=1.8Hz, 1H), 8.92 (d, J=2.3 Hz, 1H). HRMS: (ESI) m/z 355.0052 [(M+H)⁺ Calcdfor C₁₆H₁₁BrF₃N₂: 355.0052].

Example 122 (a) 5-Chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole

To a solution of 5-chloro-7-fluoro-2-pyridin-3-yl-1H-indole (Example 86,276 mg, 1.12 mmol) in DMF (4 mL) is added 60% sodium hydride in mineraloil (120 mg, 3.0 mmol) and the suspension is stirred for 30 min.Iodomethane (213 mg, 1.5 mmol) is then added to the reaction mixture andstirred at ambient temperature for 1 h. Water (2 mL) is added to quenchthe reaction. The mixture is filtered and purified by HPLC using XbridgeC18 with a gradient of acetonitrile in 0.1% NH₄OH to afford5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole. MS (ESI) m/z 261(M+H)⁺.

(b) 5-Chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile

To a solution of 5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole(130 mg, 0.50 mmol) in dichloromethane (10 mL) at ambient temperature isadded chlorosulfonyl isocyanate (282 mg, 2.0 mmol) and the mixture isstirred for 11 h, whereupon anhydrous DMF (1 mL) is added. After 1 h,the mixture is concentrated and the residue is purified by HPLC using anXbridge C18 with a gradient of acetonitrile in 0.1% NH₄OH to afford5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.89 (d, J=1.8 Hz, 3H),7.46 (dd, J=12.4, 1.8 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.71 (dd, J=7.5,4.4 Hz, 1H), 8.16 (dt, J=8.1, 2.0, 1.8 Hz, 1H), 8.83 (dd, J=4.9, 1.6 Hz,1H), 8.89 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 286.0558 [(M+H)⁺Calcd forC₁₆H₁₀ClFN₃: 286.0547].

Example 123 2-(5-Chloro-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

2-(5-Chloro-pyridin-3-yl)-1H-indole (Example 91) is processed accordingto the method described in Example 122 to give2-(5-chloro-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile. ¹H NMR (400MHz, MeOD) δ ppm 3.87 (s, 3H), 7.40 (t, J=7.6 Hz, 1H), 7.48 (ddd, J=7.7,1.3 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 8.28 (t,J=2.1 Hz, 1H), 8.70-8.90 (m, 2H). HRMS (ESI) m/z 268.0650 [(M+1-1)⁺Calcdfor C₁₆H₁₁ClN₃: 268.0641].

Example 124 2-(5-Fluoro-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

2-(5-Fluoro-pyridin-3-yl)-1H-indole (Example 92) is processed accordingto the method described in Example 122 to give2-(5-fluoro-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile. ¹H NMR (400MHz, MeOD) δ ppm 3.88 (s, 3H), 7.40 (t, J=7.6 Hz, 1H), 7.48 (ddd, J=7.8,1.1 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 8.06 (dt,J=9.0, 2.2 Hz, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.77 (s, 1H). HRMS (ESI) m/z252.0939 [(M+1-1)⁺Calcd for C₁₆H₁₁FN₃: 252.0937].

Example 125 1,5,6-Tri-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile

5,6-dimethyl-2-pyridin-3-yl-1H-indole (Example 88) is processedaccording to the method described in Example 122 to give1,5,6-tri-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile. ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.38 (s, 3H), 2.40 (s, 3H), 3.75 (s, 3H), 7.47 (s,1H), 7.54 (s, 1H), 7.67 (dd, J=7.8, 4.8 Hz, 1H), 8.14 (dt, J=8.1, 2.0,1.8 Hz, 1H), 8.78 (dd, J=4.8, 1.8 Hz, 1H), 8.88 (d, J=1.5 Hz, 1H). HRMS(ESI) m/z 262.1352 [(M+H)⁺Calcd for C₁₇H₁₆N₃: 262.1344].

Example 126 a) 6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole

A flask is charged with5-(6-chloro-1H-indol-2-yl)-pyridine-3-carbaldehyde (Example 104, 7.8 g,28.9 mmol), MeI (5.33 g, 37.5 mmol) and DMF (300 mL), and 60% NaH inmineral oil (1.386 g, 34.6 mmol) is added at 0° C. The mixture isstirred for 2 h. Water (100 mL) is added. The mixture is extracted withEtOAc twice and the combined organic phase is washed with water (2×200mL) and brine (200 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The residue is purified by silica gel chromatography with a 0 to2% methanol-DCM gradient to give6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole. MS (ESI) m/z271.0, 272.9 (M+H)⁺.

b) 6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

A flask is charged with6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole (10 g, 36.9 mmol)and acetonitrile (1 L), and chlorosulfonyl isocyanate (15.68 g, 111mmol) is added at 0° C. The mixture is stirred for 10 min. DMF (18.9 g,259 mmol) is added at 0° C. The mixture is stirred for 1.5 h. SaturatedNaHCO₃ (20 mL) and triethylamine (51.5 mL, 369 mmol) are added to thereaction mixture, which is stirred for 10 min. The mixture isconcentrated in vacuo to give a residue which is purified by silica gelflash chromatography eluting with a 0 to 5% methanol-DCM gradient togive6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile. MS(ESI) m/z 296.0, 297.8 (M+H)⁺.

Example 127 2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

5-(1H-indol-2-yl)-pyridine-3-carbaldehyde (Example 103) is processedaccording to the method described in Example 122 using acetonitrileinstead of dichloromethane, to give2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile. MS (ESI)m/z 262.02 (M+H)⁺.

Example 128 2-(4-Chloro-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

A flask is charged with 2-(4-chloro-pyridin-3-yl)-1-methyl-1H-indole(Example 107, 0.110 g, 0.418 mmol) and dichloromethane (5 mL).Chlorosulfonyl isocyanate (0.091 mL, 1.04 mmol) is added and thereaction is stirred for 2 min, whereupon DMF (1 mL) is added. Afteranother 20 min, the reaction is concentrated in vacuo and the residue ispurified by reverse phase HPLC with Xbridge Shield RP18 column and a0.1% aqueous NH₄OH in acetonitrile gradient to afford2-(4-chloro-pyridin-3-yl)-1H-indole-3-carbonitrile as a solid. ¹H NMR(400 MHz, MeOD) δ ppm 3.74 (s, 3H), 7.41 (t, J=7.6 Hz, 1H), 7.49 (t,J=7.7 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.84 (d,J=5.3 Hz, 1H), 8.61-8.86 (m, 2H). HRMS (ESI) m/z 268.0635 [(M+H)⁺Calcdfor C₁₅H₁₁ClN₃: 268.0641].

Example 129 2-(5-Methoxy-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

2-(5-Methoxy-pyridin-3-yl)-1-methyl-1H-indole (Example 101) is processedaccording to the method described in Example 128 to give2-(5-methoxy-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile. ¹H NMR(400 MHz, MeOD) δ ppm 3.87 (s, 3H), 4.02 (s, 3H), 7.36-7.42 (m, 1H),7.47 (td, J=7.8, 1.1 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.72-7.77 (m, 2H),8.45 (d, J=1.8 Hz, 1H), 8.49 (d, J=2.8 Hz, 1H). HRMS (ESI) m/z 264.1130[(M+H)⁺Calcd for C₁₆H₁₄N₃O: 264.1137].

Example 1302-(5-Benzyloxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile

2-(5-Benzyloxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole (Example 109)is processed according to the method described in Example 128 to give2-(5-benzyloxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile.¹H NMR (400 MHz, MeOD) δ ppm 3.75 (s, 3H), 5.33 (s, 2H), 7.37 (dd,J=8.3, 1.8 Hz, 2H), 7.44 (t, J=7.3 Hz, 2H), 7.54 (d, J=7.1 Hz, 2H), 7.71(d, J=8.3 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.78 (dd, J=2.8, 1.8 Hz, 1H),8.45 (d, J=1.8 Hz, 1H), 8.56 (d, J=2.8 Hz, 1H). HRMS (ESI) m/z 374.1070[(M+H)⁺ Calcd for C₂₂H₁₇ClN₃O: 374.1060].

Example 1312-(5-Ethoxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile

2-(5-Ethoxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole (Example 110) isprocessed according to the method described in Example 128 to give2-(5-ethoxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile. ¹HNMR (400 MHz, MeOD) δ ppm 1.51 (t, J=7.1 Hz, 3H), 3.84 (s, 3H), 4.27 (q,J=6.9 Hz, 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.66-7.74 (m, 2H), 7.76 (d,J=1.5 Hz, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.47 (d, J=2.8 Hz, 1H). HRMS(ESI) m/z 312.0893 [(M+H)⁺Calcd for C₁₇H₁₆ClN₃O: 312.0904].

Example 1326-Chloro-2-(5-methyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

6-Chloro-2-(5-methyl-pyridin-3-yl)-1-methyl-1H-indole (Example 111) isprocessed according to the method described in Example 128 to give6-chloro-2-(5-methyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.44 (s, 3H), 3.78 (s, 3H), 7.36 (dd,J=8.3, 1.8 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.97(s, 1H), 8.65 (d, J=1.5 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z282.0803 [(M+H)⁺Calcd for C₁₆H₁₃ClN₃: 282.0798].

Example 1336-Chloro-2-(5-trifluoromethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

6-Chloro-2-(5-trifluoromethyl-pyridin-3-yl)-1-methyl-1H-indole (Example112) is processed according to the method described in Example 128 togive6-chloro-2-(5-trifluoromethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.82 (s, 3H), 7.39 (dd, J=8.5, 1.9 Hz,1H), 7.76 (d, J=8.3 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H), 8.65 (s, 1H), 9.22(d, J=2.0 Hz, 1H), 9.23 (d, J=1.3 Hz, 1H). HRMS (ESI) m/z 377.0790[(M+H+CH₃CN)⁺Calcd for C₁₈H₁₃ClF₃N₄: 377.0781].

Example 1345-Fluoro-2-(5-fluoro-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

5-Fluoro-2-(5-fluoro-pyridin-3-yl)-1-methyl-1H-indole (Example 118) isprocessed according to the method described in Example 128 to give5-fluoro-2-(5-fluoro-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile. ¹HNMR (400 MHz, MeOD) δ ppm 3.87 (s, 3H), 7.26 (td, J=9.2, 2.4 Hz, 1H),7.44 (dd, J=8.7, 2.4 Hz, 1H), 7.70 (dd, J=9.1, 4.3 Hz, 1H), 8.06 (dt,J=9.0, 2.4, 2.3 Hz, 1H), 8.72-8.79 (m, 2H). HRMS (ESI) m/z 270.0831[(M+H)⁺Calcd for C₁₆H₁₀F₂N₃: 270.0843].

Example 135 5-(3-Cyano-1-methyl-1H-indol-2-yl)-nicotinic acid ethylester

The product in Example 102 is processed according to the methoddescribed in Example 128 to give5-(3-cyano-1-methyl-1H-indol-2-yl)-nicotinic acid ethyl ester. ¹H NMR(400 MHz, MeOD) δ ppm 1.47 (t, J=7.1 Hz, 3H), 3.88 (s, 3H), 4.51 (q,J=7.2 Hz, 2H), 7.40 (t, J=7.6 Hz, 1H), 7.49 (td, J=7.7, 1.3 Hz, 1H),7.69 (d, J=8.3 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 8.69 (t, J=2.0 Hz, 1H),9.09 (d, J=2.0 Hz, 1H), 9.34 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 306.1246[(M+H)⁺ Calcd for C₁₈H₁₆N₃O₂: 306.1243].

Example 136 6-Chloro-2-pyridin-3-yl-1-methyl-1H-indole-3-carbonitrile

The product in Example 113 is processed according to the methoddescribed in Example 128 to give6-chloro-2-pyridin-3-yl-1-methyl-1H-indole-3-carbonitrile. ¹H NMR (400MHz, DMSO-d₆) δ ppm 3.79 (s, 3H), 7.37 (dd, J=8.5, 1.9 Hz, 1H), 7.69(dd, J=7.5, 4.4 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H),8.17 (dt, J=8.1, 2.0, 1.8 Hz, 1H), 8.82 (dd, J=4.9, 1.6 Hz, 1H), 8.90(d, J=1.5 Hz, 1H). HRMS (ESI) m/z 268.0653 [(M+H)⁺Calcd for C₁₆H₁₁ClN₃:268.0642].

Example 137 (a) 1-Methyl-2-(5-ethyl-pyridin-3-yl)-1H-indole

To a solution of 1-methyl-2-(5-vinyl-pyridin-3-yl)-1H-indole (Example105, 0.473 g, 2.02 mmol) in methanol (10 mL) is added palladium oncarbon (0.215 g, 0.202 mmol). The reaction mixture is stirred at 55° C.under H₂ for 16 h. It is then cooled to room temperature and filteredthrough celite. The celite layer is washed with methanol thoroughly andthe combined filtrate is concentrated in vacuo. The residue is purifiedby silica gel flash chromatography (heptane-ethyl acetate, 3:1) toafford 1-methyl-2-(5-ethyl-pyridin-3-yl)-1H-indole as a yellow oil. MS(ESI) m/z 237.24 (M+H)⁺.

(b) 2-(5-Ethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

1-Methyl-2-(5-ethyl-pyridin-3-yl)-1H-indole is processed according tothe method described in Example 128 to give2-(5-ethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile. ¹H NMR (400MHz, MeOD) δ ppm 1.40 (t, J=7.6 Hz, 3H), 2.89 (q, J=7.7 Hz, 2H), 3.87(s, 3H), 7.35-7.43 (m, 1H), 7.43-7.50 (m, 1H), 7.67 (d, J=8.3 Hz, 1H),7.75 (dd, J=7.9, 0.8 Hz, 1H), 8.06 (t, J=2.1 Hz, 1H), 8.66 (d, J=1.9 Hz,1H), 8.70 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 262.1351 [(M+H)⁺Calcd forC₁₇H₁₆N₃: 262.1344].

Example 138 (a) Methanesulfonic acid 5-bromo-pyridin-3-yl ester

A flask is charged with 5-bromo-pyridin-3-ol (0.200 g, 1.126 mmol),potassium carbonate (0.212 g, 1.487 mmol) and acetone (3 mL).Methanesulfonyl chloride (0.143 g, 1.239 mmol) is then added dropwise.After 2 h, an other portion of methanesulfonyl chloride (0.071 g, 0.61mmol) is added. After overnight stirring, the suspension isconcentrated, diluted with ethyl acetate and filtered through a pad ofsilica gel. The filtrate is concentrated in vacuo to give a residue,which is purified by silica gel flash chromatography (heptane-ethylacetate, 4:1 to 7:3) to give a mixture of product and starting material.The fractions are combined, washed three times with saturated aqueoussodium bicarbonate and dried over MgSO₄. Concentration in vacuo givesmethanesulfonic acid 5-bromo-pyridin-3-yl ester as an oil. ¹H NMR (400MHz, CDCl₃) δ ppm 3.25 (s, 3H), 7.86 (m, 1H), 8.52 (d, J=2.3 Hz, 1H),8.67 (d, J=1.8 Hz, 1H).

(b) Methanesulfonic acid 5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

Methanesulfonic acid 5-bromo-pyridin-3-yl ester is processed accordingto the method described in Example 100 to give methanesulfonic acid5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. (ESI) m/z 303.1 (M+H)⁺.

(c) Methanesulfonic acid 5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylester

Methanesulfonic acid 5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester isprocessed according to the method described in Example 128 to givemethanesulfonic acid 5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylester. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.57 (s, 3H), 3.84 (s, 3H),7.35-7.40 (m, 1H), 7.43-7.48 (m, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.79 (d,J=8.3 Hz, 1H), 8.30 (t, J=2.5 Hz, 1H), 8.85 (d, J=2.5 Hz, 1H), 8.94 (d,J=1.8 Hz, 1H). HRMS (ESI) m/z 328.0771 [(M+H)⁺Calcd for C₁₆H₁₄N₃O₃S:328.0756].

Example 139 (a) Dimethyl-sulfamic acid 5-bromo-pyridin-3-yl ester

A flask is charged with 5-bromo-pyridin-3-ol (0.200 g, 1.126 mmol),potassium phosphate (0.631 g, 2.884 mmol) and acetone (5 mL) and cooledto 0° C. Dimethylsulfamoyl chloride (0.261 g, 1.802 mmol) is then addeddropwise and the cooling bath is removed. After 2 h, the mixture isdiluted with acetone, filtered and the filtrate is concentrated invacuo. The residue is dissolved in THF (30 mL) and polymer-supportedtrisamine (3.85 mmol/g, 0.7 g, 2.7 mmol) is added. After 1 h, themixture is filtered. Concentration in vacuo gives a residue which ispurified by silica gel flash chromatography (heptane-ethyl acetate, 9:1to 4:1) to give dimethyl-sulfamic acid 5-bromo-pyridin-3-yl ester as asolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.05 (s, 3H), 7.86 (m, 1H), 8.50(d, J=2.3 Hz, 1H), 8.62 (d, J=1.9 Hz, 1H).

(b) Dimethyl-sulfamic acid 5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

Dimethyl-sulfamic acid 5-bromo-pyridin-3-yl ester is processed accordingto the method described in Example 100 to give dimethyl-sulfamic acid5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. MS (ESI) m/z 332.1(M+H)⁺.

(c) Dimethyl-sulfamic acid5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

Dimethyl-sulfamic acid 5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester isprocessed according to the method described in Example 128 to givedimethyl-sulfamic acid 5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylester. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.99 (s, 6H), 3.82 (s, 3H),7.35-7.40 (m, 1H), 7.43-7.48 (m, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.79 (d,J=8.3 Hz, 1H), 8.24 (dd, J=2.5, 1.8 Hz, 1H), 8.85 (d, J=2.5 Hz, 1H),8.91 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 357.1018 [(M+H)⁺Calcd forC₁₇H₁₇N₄O₃S: 357.1021].

Example 140 6-Fluoro-2-pyridin-3-yl-1H-indole-3-carbonitrile

To a solution of 6-fluoro-2-pyridin-3-yl-1H-indole (Example 89, 212 mg,1.0 mmol) in dichloromethane (90 mL) at ambient temperature is addedchlorosulfonyl isocyanate (0.71 g, 5 mmol) and the mixture is stirredovernight. Anhydrous DMF (1 mL) is added. After 1 h, the solvent isremoved in vacuo and the residue purified by HPLC using an Xbridge C18with a gradient of acetonitrile in 0.1% NH₄OH to give6-fluoro-2-pyridin-3-yl-1H-indole-3-carbonitrile as a white solid. ¹HNMR (400 MHz, DMSO-d₆) d ppm 7.12-7.21 (m, 1H), 7.39 (dd, J=9.5, 2.4 Hz,1H), 7.64-7.74 (m, 2H), 8.27-8.35 (m, 1H), 8.73 (dd, J=4.9, 1.6 Hz, 1H),9.14 (d, J=1.8 Hz, 1H), 12.89 (s, 1H). MS (ESI) m/z 238.0 (M+H)⁺.

Example 141 2-Pyridin-3-yl-1H-indole-3,5-dicarbonitrile

2-Pyridin-3-yl-1H-indole-5-carbonitrile (Example 8) is processedaccording to the method described in Example 140, using acetonitrileinstead of dichloromethane, to give2-pyridin-3-yl-1H-indole-3,5-dicarbonitrile. ¹H NMR (400 MHz, MeOD) δppm 7.68 (dd, J=8.6 Hz, 1H), 7.72 (dd, J=8.1, 4.8 Hz, 1H), 7.75 (d,J=8.3 Hz, 1H), 8.17 (s, 1H), 8.47 (dt, J=8.1, 1.9 Hz, 1H), 8.76 (dd,J=4.8, 1.5 Hz, 1H), 9.19 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 245.0823[(M+H)+calcd for C₁₅H₉N₄: 245.0827].

Example 142 5-Chloro-2-pyridin-3-yl-1H-indole-3-carbonitrile

5-Chloro-2-pyridin-3-yl-1H-indole (Example 87) is processed according tothe method described in Example 140, using acetonitrile instead ofdichloromethane, to give5-chloro-2-pyridin-3-yl-1H-indole-3-carbonitrile. ¹H NMR (400 MHz, MeOD)δ ppm 7.36 (dd, J=8.6, 2.0 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.65-7.77(m, 2H), 8.43 (dt, J=8.1, 2.0 Hz, 1H), 8.72 (d, J=4.8 Hz, 1H), 9.16 (s,1H). HRMS (ESI) m/z 254.0495 [(M+H)⁺ calcd for C₁₄H₉ClN₃: 254.0485].

Example 143 2-(4-Methoxy-pyridin-3-yl)-1H-indole-3,5-dicarbonitrile

2-(4-Methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile (Example 128) isprocessed according to the method described in Example 140, usingacetonitrile instead of dichloromethane, to give2-(4-methoxy-pyridin-3-yl)-1H-indole-3,5-dicarbonitrile. MS (ESI) m/z275.08 (M+H)⁺.

Example 144 2-(5-Fluoro-pyridin-3-yl)-1H-indole-3-carbonitrile

2-(5-Fluoro-pyridin-3-yl)-1H-indole (Example 92) is processed accordingto the method described in Example 140, using a mixture ofdichloromethane and acetonitrile instead of dichloromethane, to give2-(5-fluoro-pyridin-3-yl)-1H-indole-3-carbonitrile. MS (ESI) m/z 238.0(M+H)⁺.

Example 145 6-Fluoro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile

A flask is charged with 6-fluoro-2-pyridin-3-yl-1H-indole-3-carbonitrile(Example 140, 50 mg, 0.21 mmol) and DMF (2 mL), and 60% sodium hydride(25 mg, 0.63 mmol) is added. The mixture is stirred at room temperaturefor 30 min before addition of iodomethane (45 mg, 0.315 mmol). After 1h, saturated NaHCO₃ aqueous solution (3 mL) is added to quench thereaction and the mixture is filtered and purified on Xbridge C18 elutingwith a 9:1 to 1:9 water-acetonitrile gradient to give6-fluoro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile. ¹H NMR (400MHz, DMSO-d₆) δ ppm 3.77 (s, 3H), 7.19-7.26 (m, 1H), 7.66-7.76 (m, 3H),8.14-8.19 (m, 1H), 8.80 (dd, J=4.9, 1.6 Hz, 1H), 8.89 (dd, J=2.3, 0.8Hz, 1H). HRMS (ESI) m/z 293.1210 [(M+H+CH₃CN)⁺ calcd for C₁₇H₁₄FN₄:293.1203].

Example 146 1-Methyl-2-pyridin-3-yl-1H-indole-3,5-dicarbonitrile

2-Pyridin-3-yl-1H-indole-3,5-dicarbonitrile (Example 141) is processedaccording to the method described in Example 145 to give1-methyl-2-pyridin-3-yl-1H-indole-3,5-dicarbonitrile. ¹H NMR (400 MHz,MeOD) δ ppm 3.90 (s, 3H), 7.65-7.79 (m, 2H), 7.87 (d, J=8.6 Hz, 1H),8.20 (s, 1H), 8.22 (dt, J=8.0, 1.9, 1.8 Hz, 1H), 8.83 (dd, J=4.9, 1.6Hz, 1H), 8.92 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 259.0979 [(M+H)⁺ calcdfor C₁₆H₁₁N₄: 259.0984].

Example 147 5-Chloro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile

5-Chloro-2-pyridin-3-yl-1H-indole-3-carbonitrile (Example 142) isprocessed according to the method described in Example 145 to give5-chloro-1-methyl-2-pyridin-3-yl-1H-indole-3-carbonitrile. ¹H NMR (400MHz, MeOD) δ ppm 3.86 (s, 3H), 7.44 (dd, J=8.8, 2.0 Hz, 1H), 7.68 (d,J=8.8 Hz, 1H), 7.71-7.81 (m, 2H), 8.20 (dt, J=8.0, 1.9 Hz, 1H), 8.81(dd, J=4.9, 1.6 Hz, 1H), 8.89 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 268.0646[(M+H)⁺ calcd for C₁₅H₁₁ClN₃: 268.0641].

Example 1481-Methyl-2-(4-methoxy-pyridin-3-yl)-1H-indole-3,5-dicarbonitrile

2-(4-methoxy-pyridin-3-yl)-1H-indole-3,5-dicarbonitrile (Example 143) isprocessed according to the method described in Example 145 to give1-methyl-2-(4-methoxy-pyridin-3-yl)-1H-indole-3,5-dicarbonitrile. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 3.69 (s, 3H), 3.94 (s, 3H), 7.38 (d, J=5.8 Hz,1H), 7.79 (dd, J=8.6, 1.5 Hz, 1H), 7.95 (dd, J=8.7, 0.6 Hz, 1H), 8.27(dd, J=1.5, 0.6 Hz, 1H), 8.57 (s, 1H), 8.72 (d, J=5.8 Hz, 1H). HRMS(ESI) m/z 289.1096 [(M+H)⁺ calcd for C₁₇H₁₃N₄O: 289.1089].

Example 149 1-Methyl-2-(5-fluoro-pyridin-3-yl)-1H-indole-3-carbonitrile

2-(5-Fluoro-pyridin-3-yl)-1H-indole-3-carbonitrile (Example 144) isprocessed according to the method described in Example 145 to give1-methyl-2-(5-fluoro-pyridin-3-yl)-1H-indole-3-carbonitrile. ¹H NMR (400MHz, DMSO-d₆) δ ppm 3.80 (s, 3H), 7.30 (td, J=9.3, 2.5 Hz, 1H), 7.52(dd, J=9.0, 2.4 Hz, 1H), 7.69 (dd, J=8.0, 4.9 Hz, 1H), 7.82 (dd, J=9.1,4.3 Hz, 1H), 8.17 (dt, J=8.1, 2.0, 1.8 Hz, 1H), 8.81 (dd, J=4.8, 1.5 Hz,1H), 8.90 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 252.0948 [(M+H)⁺ calcd forC₁₆H₁₁FN₃: 252.0937].

Example 150 (a) 1-(5-Bromo-pyridin-3-ylmethyl)-morpholine

To a solution of 3-bromo-5-carboxaldehyde pyridine (0.400 g, 2.086 mmol)in dichloroethane (10 mL) at 0° C. is added morpholine (0.275 g, 3.129mmol), followed with Na(OAc)₃BH (0.931 g, 4.172 mmol). After 2 h, thecooling bath is removed. After stirring overnight, the mixture isdiluted with dichloromethane (0.2 L) and washed twice with water andbrine. The combined aqueous phase is extracted (twice) withdichloromethane. The combined organic phase is dried over MgSO₄,filtered and concentrated to give a residue which is purified by silicagel flash chromatography (dichloromethane-methanol, 99:1 to 49:1) gives1-(5-bromo-pyridin-3-ylmethyl)-morpholine as a colorless oil. MS (ESI)m/z 257 and 259 (M+H)⁺.

(b) 6-Chloro-2-(5-morpholin-4-ylmethyl-pyridin-3-yl)-1H-indole

1-(5-Bromo-pyridin-3-ylmethyl)-morpholine and6-chloro-1-Boc-indole-2-boronic acid are processed according to themethod described in Example 91 to give6-chloro-2-(5-morpholin-4-ylmethyl-pyridin-3-yl)-1H-indole. MS (ESI) m/z328.2 (M+H)⁺.

(c) 6-Chloro-1-methyl-2-(5-morpholin-4-ylmethyl-pyridin-3-yl)-1H-indole

6-chloro-2-(5-morpholin-4-ylmethyl-pyridin-3-yl)-1H-indole is processedaccording to the method described in Example 109 to afford6-chloro-1-methyl-2-(5-morpholin-4-ylmethyl-pyridin-3-yl)-1H-indole. ¹HNMR (400 MHz, MeOD) δ ppm 2.52-2.60 (m, 4H), 3.70 (s, 2H), 3.72-3.77 (m,4H), 3.79 (s, 3H), 6.70 (s, 1H), 7.11 (dd, J=8.3, 1.8 Hz, 1H), 7.53 (s,1H), 7.59 (d, J=8.6 Hz, 1H), 8.06 (t, J=2.0 Hz, 1H), 8.60 (d, J=1.8 Hz,1H), 8.69 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 342.1369 [(M+H)⁺Calcd forC₁₉H₂₁ClN₃O: 342.1373].

Example 151 (a) 1-(5-Bromo-pyridin-3-ylmethyl)-4-methyl-piperazine

To a solution of 3-bromo-5-carboxaldehyde pyridine (0.400 g, 2.086 mmol)in dichloroethane (10 mL) at 0° C. is added 1-methylpiperazine (0.317 g,3.129 mmol), followed with Na(OAc)₃BH (0.931 g, 4.172 mmol). After 2 h,the cooling bath is removed. After stirring overnight, the mixture isdiluted with dichloromethane (0.2 L) and washed with saturated aqueoussodium bicarbonate. The organic phase is dried over MgSO₄, filtered andconcentrated to give 1-(5-bromo-pyridin-3-ylmethyl)-4-methyl-piperazineas a yellow solid. (ESI) m/z 270 and 272 (M+H)⁺.

(b)6-Chloro-2-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole

1-(5-Bromo-pyridin-3-ylmethyl)-4-methyl-piperazine and6-chloro-1-Boc-indole-2-boronic acid are processed according to themethod described in Example 91 to give6-chloro-2-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole.(ESI) m/z 341.1 (M+H)⁺.

(c)6-Chloro-1-methyl-2-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole

6-Chloro-1-methyl-2-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indoleis processed according to the method described in Example 109 to afford6-chloro-1-methyl-2-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole.¹H NMR (400 MHz, MeOD) δ ppm 2.33 (s, 3H), 2.60 (br. s., 8H), 3.73 (s,2H), 3.79 (s, 3H), 6.70 (s, 1H), 7.11 (dd, J=8.5, 1.9 Hz, 1H), 7.53 (d,J=1.8 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 8.05 (t, J=2.0 Hz, 1H), 8.59 (d,J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 355.1688[(M+H)⁺Calcd for C₂₀H₂₄ClN₄: 355.1689].

Example 1526-Chloro-1-methyl-2-(5-morpholin-4-ylmethyl-pyridin-3-yl)-1H-indole-3-carbonitrile

6-Chloro-1-methyl-2-(5-morpholin-4-ylmethyl-pyridin-3-yl)-1H-indole(Example 150) is processed according to the method described in Example128 to give6-chloro-1-methyl-2-(5-morpholin-4-ylmethyl-pyridin-3-yl)-1H-indole-3-carbonitrile.¹H NMR (400 MHz, MeOD) δ ppm 2.51-2.66 (m, 4H), 3.69-3.79 (m, 6H), 3.85(s, 3H), 7.38 (dd, J=8.3, 1.8 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.77 (d,J=1.5 Hz, 1H), 8.20 (t, J=2.0 Hz, 1H), 8.77 (dd, J=13.3, 2.1 Hz, 2H).HRMS (ESI) m/z 367.1321 [(M+H)⁺Calcd for C₂₀H₂₀ClN₄O: 367.1326].

Example 1536-Chloro-1-methyl-2-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole-3-carbonitrile

6-Chloro-1-methyl-2-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole(Example 151) is processed according to the method described in Example128 to give6-chloro-1-methyl-2-[5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole-3-carbonitrile.¹H NMR (400 MHz, MeOD) δ ppm 2.34 (s, 3H), 2.61 (br. s., 8H), 3.77 (s,2H), 3.85 (s, 3H), 7.38 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H),7.77 (d, J=1.5 Hz, 1H), 8.18 (t, J=2.0 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H),8.79 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 380.1624 [(M+H)⁺ Calcd forC₂₁H₂₃ClN₅: 380.1642].

Example 154 (a)2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-1-methyl-1H-indole

A flask is charged with[3-(1-methyl-1H-indol-2-yl)-pyridin-4-yl]-methanol (Example 106, 0.270g, 1.13 mmol), tent-butyl di-methylsilyl chloride (0.187 g, 1.24 mmol),imidazole (0.231 g, 3.39 mmol), DMAP (0.025 g, 0.193 mmol) and DMF (3mL). The reaction is stirred at room temperature for 3 h. Water is addedand the mixture is extracted with ethyl acetate. The combined organiclayer is dried over sodium sulfate and concentrated in vacuo to afford2-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-1-methyl-1H-indoleas an oil, which is used in the next step with no further purification.MS (ESI) m/z 353.31 (M+H)⁺

(b) 2-(4-Hydroxymethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

To a solution of2-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-1-methyl-1H-indole(0.263 g, 0.747 mmol) in DCM (5 mL) is added chlorosulfonyl isocyanate(0.162 mL, 1.867 mmol). After 5 min, DMF (1 mL) is added. After another30 min, the reaction is concentrated under vacuo to afford2-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrileas a light yellow solid, which is redissolved in DCM (3 mL). 4 M HCl in1,4-dioxane (1 mL) is added, and the mixture is stirred at roomtemperature for 30 min. Purification by reverse phase HPLC with XbridgeShield RP18 column and a 0.1% aqueous NH₄OH in acetonitrile gradientaffords2-(4-hydroxymethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile as asolid. ¹H NMR (400 MHz, MeOD) δ ppm 3.67 (s, 3H), 4.44-4.67 (m, 2H),7.39 (t, J=7.6 Hz, 1H), 7.47 (t, J=8.3 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H),7.74 (d, J=7.8 Hz, 1H), 7.87 (d, J=5.3 Hz, 1H), 8.60 (s, 1H), 8.80 (d,J=5.3 Hz, 1H). HRMS (ESI) m/z 264.1142 [(M+1-1)⁺Calcd for C₁₆H₁₄N₃O:264.11379].

Example 155 3-Bromo-2-(4-hydroxy-pyridin-3-yl)-1H-indole-5-carbonitrile

A flask is charged with2-(4-methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile (Example 90, 190 mg,0.80 mmol) and DCE (8 mL), and 1.0 M BBr₃ in DCM (4.8 mL, 4.8 mmol) isadded. The mixture is stirred at room temperature overnight. Thereaction mixture is poured into saturated aqueous NaHCO₃ and extractedwith DCM. The aqueous phase is concentrated, acidified with 1M HCl inwater and concentrated in vacuo. The residue is purified with an XbridgeC18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give3-bromo-2-(4-hydroxy-pyridin-3-yl)-1H-indole-5-carbonitrile. ¹H NMR (400MHz, DMSO-d₆) δ ppm 6.40 (d, J=7.1 Hz, 1H), 7.48 (dd, J=8.5, 1.6 Hz,1H), 7.71 (d, J=8.6 Hz, 1H), 7.81 (dd, J=7.1, 1.3 Hz, 1H), 7.86 (d,J=1.0 Hz, 1H), 8.67 (d, J=1.3 Hz, 1H). HRMS (ESI) m/z 313.9932 [(M+H)⁺calcd for C₁₄H₉BrN₃O: 313.9929].

Example 156 (a) 5-(1-Methyl-1H-indol-2-yl)-nicotinic acid

To a solution of 5-(1-methyl-1H-indol-2-yl)-nicotinic acid ethyl ester(Example 102, 0.156 g, 0.55 mmol) and MeOH (5 mL) is added aqueous 1MLiOH (1.4 mL, 1.39 mmol). The reaction is stirred at room temperaturefor 2.5 h. Purification by reverse phase HPLC with Xbridge Shield RP18column and a 0.1% aqueous NH₄OH in acetonitrile gradient gives5-(1-methyl-1H-indol-2-yl)-nicotinic acid. MS (ESI) m/z 253.34 (M+H)⁺.

(b) 5-(1-Methyl-1H-indol-2-yl)-nicotinamide

A flask is charged with 5-(1-methyl-1H-indol-2-yl)-nicotinic acid (0.037g, 0.146 mmol), HOBT (0.024 g, 0.175 mmol), EDCI (0.034 g, 0.175 mmol),DIPEA (0.076 mL, 0.439 mmol) and DMF (3 mL). Ammonium chloride (0.012 g,0.219 mmol) is added and the reaction is stirred at room temperatureovernight. Purification by reverse phase HPLC with Xbridge Shield RP18column and a 0.1% aqueous NH₄OH in acetonitrile gradient gives5-(1-methyl-1H-indol-2-yl)-nicotinamide. ¹H NMR (400 MHz, MeOD) δ ppm3.85 (s, 3H), 6.77 (d, J=0.6 Hz, 1H), 7.08-7.19 (m, 1H), 7.29 (ddd,J=8.2, 7.1, 1.1 Hz, 1H), 7.50 (dd, J=8.3, 0.7 Hz, 1H), 7.65 (d, J=8.0Hz, 1H), 8.49 (t, J=2.1 Hz, 1H), 8.95 (d, J=2.1 Hz, 1H), 9.09 (d, J=2.1Hz, 1H). HRMS (ESI) m/z 252.1145 [(M+H)⁺Calcd for C₁₅H₁₄N₃O: 252.1137].

Example 157 2-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yloxy]-ethanol

To a solution of 5-(1-methyl-1H-indol-2-yl)-pyridin-3-ol (Example 108,0.300 g, 1.33 mmol), potassium carbonate (0.462 g, 3.34 mmol) and DMF (3mL) is added (2-chloro-ethoxy)-trimethylsilane (0.324 mL, 2.00 mmol) andthe reaction is stirred at 70° C. overnight and at 100° C. for another24 h. It is then cooled to room temperature, diluted with ethyl acetateand washed with water. The organic layer is dried over sodium sulfateand concentrated in vacuo to afford a residue which is purified byreverse phase HPLC with Xbridge Shield RPI 8 column and a gradient of0.1% aqueous NH₄OH in acetonitrile. The resulting oil is dissolved indiethyl ether and a few drops of concentrated HCl are added.Lyophilization gives2-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yloxy]-ethanol as the HCl salt.¹H NMR (400 MHz, MeOD) δ ppm (HCl salt) 3.78 (s, 3H), 3.93 (t, J=4.8 Hz,2H), 4.22 (t, J=4.5 Hz, 2H), 6.65 (s, 1H), 7.09 (t, J=7.5 Hz, 1H), 7.23(ddd, J=7.6, 1.1 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.58 (d, J=7.8 Hz,1H), 7.62 (dd, J=2.8, 1.8 Hz, 1H), 8.31 (d, J=2.8 Hz, 1H), 8.34 (d,J=1.5 Hz, 1H). HRMS (ESI) m/z 269.1302 [(M+H)⁺ Calcd for C₁₆H₁₇N₂O₂:269.1290].

Example 158 (a) 6-Chloro-2-(5-hydroxy-pyridin-3-yl)-indole-1-carboxylicacid tert-butyl ester

A microwave flask is charged with 6-chloro-1-Boc-indole-2-boronic acid(1.91 g, 6.46 mmol), 3-hydroxy-5-bromopyridine (0.750 g, 4.31 mmol),potassium phosphate (1.83 g, 8.62 mmol) and DMF (15 mL). The flask isevacuated and filled with nitrogen thrice and Pd(PPh₃)₄ (0.250 g, 0.215mmol) is added. The flask is evacuated and filled with nitrogen thriceagain, and heated to 110° C. under microwave irradiation for 45 min.Pd(PPh₃)₄ (0.100 g, 0.086 mmol) is added and the vial is heated again to110° C. under microwave irradiation for 45 min. The mixture is thendiluted with ethyl acetate and washed with water thrice. The organiclayer is dried over sodium sulfate and concentrated in vacuo. Theresidue is purified by silica gel flash chromatography(dichloromethane-methanol, 19:1) to afford6-chloro-2-(5-hydroxy-pyridin-3-yl)-indole-1-carboxylic acid tert-butylester as a solid. MS (ESI) m/z 345.06 (M+H)⁺

(b) 6-Chloro-2-(5-diethylsulfamoyloxy-pyridin-3-yl)-indole-1-carboxylicacid tert-butyl ester

A flask is charged with6-chloro-2-(5-hydroxy-pyridin-3-yl)-indole-1-carboxylic acid tert-butylester (0.200 g, 0.581 mmol) and acetone (5 mL). Diethylaminosulfamoylchloride (0.150 g, 0.872 mmol) and potassium phosphate (0.308 g, 1.45mmol) are added and the reaction is stirred at room temperatureovernight. The mixture is then concentrated in vacuo. The residue isdissolved in DCM and washed with water. The organic layer is dried oversodium sulfate and concentrated to afford6-chloro-2-(5-diethylsulfamoyloxy-pyridin-3-yl)-indole-1-carboxylic acidtert-butyl ester as an oil, which is used without further purification.MS (ESI) m/z 480.1 (M+H)⁺.

(c) Diethyl-sulfamic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester

6-Chloro-2-(5-diethylsulfamoyloxy-pyridin-3-yl)-indole-1-carboxylic acidtert-butyl ester is redissolved in DCM (2 mL) and trifluoroacetic acid(2 mL) is added. After 1 h, saturated aqueous sodium bicarbonate isadded and following extraction with dichloromethane, the organic layeris dried over sodium sulfate and concentrated to give diethyl-sulfamicacid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester, which is used in thenext step without further purification. MS (ESI) m/z 378.1 (M+H)⁺

(d) Diethyl-sulfamic acid5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

A flask is charged with diethyl-sulfamic acid5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester (0.175 g, 0.560 mmol) andDMF (5 mL). Dimethyl carbonate (0.116 mL, 1.38 mmol) and potassiumcarbonate (0.035 g, 0.253 mmol) are added and the reaction is stirred at150° C. overnight. The reaction mixture is cooled to room temperature,diluted with ethyl acetate and washed with water. The organic layer isdried over sodium sulfate and concentrated in vacuo. The residue ispurified by flash chromatography (heptane-ethyl acetate, 3:1) to afforddiethyl-sulfamic acid 5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylester as a yellow solid. MS (ESI) m/z 394.04 (M+H)⁺

(e) Diethyl-sulfamic acid5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

Diethyl-sulfamic acid 5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylester is processed according to the method described in Example 128 togive diethyl-sulfamic acid5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. ¹H NMR(400 MHz, MeOD) δ ppm 1.28 (t, J=7.2 Hz, 6H), 3.51 (q, J=7.1 Hz, 4H),3.85 (s, 3H), 7.39 (dd, J=8.5, 1.9 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.78(d, J=1.8 Hz, 1H), 8.15 (t, J=2.0 Hz, 1H), 8.77 (d, J=2.5 Hz, 1H), 8.84(d, J=1.8 Hz, 1H). HRMS (ESI) m/z 419.0966 [(M+H)⁺Calcd forC₁₉H₂₀ClN₄O₃S: 419.0945].

Example 159 (a) N-Ethyl-N-benzylaminosulfamoyl chloride

To a solution of sulfuryl chloride (1.19 mL, 14.8 mmol) indichloromethane (10 mL) is added N-ethyl-N-benzylamine (2.0 g, 14.7mmol) at −10° C. The cooling bath is removed after 30 min and themixture is stirred overnight. The mixture is washed with water andfollowing back-extraction with DCM, the combined organic layer is driedover sodium sulfate and concentrated in vacuo to giveN-ethyl-N-benzylaminosulfamoyl chloride. ¹H NMR (400 MHz, CDCl₃) δ ppm1.19 (t, J=7.2 Hz, 3H), 3.40 (q, J=7.3 Hz, 2H), 4.50 (br. s., 2H),7.32-7.48 (m, 5H).

(b) Benzyl-ethyl-sulfamic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-ylester

N-Ethyl-N-benzylaminosulfamoyl chloride and6-chloro-2-(5-hydroxy-pyridin-3-yl)-indole-1-carboxylic acid tert-butylester (Example 158a) are processed according to the method described inExample 158b to give2-[5-(benzyl-ethyl-sulfamoyloxy)-pyridin-3-yl]-6-chloro-indole-1-carboxylicacid tert-butyl ester. The crude product is loaded onto silica gel andheated to 50° C. overnight under vacuum. Elution with heptane-ethanol,1:1 affords benzyl-ethyl-sulfamic acid5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester. MS (ESI) m/z 442.1(M+H)⁺.

(c) Benzyl-ethyl-sulfamic acid5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

Benzyl-ethyl-sulfamic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl esteris processed according to the method described in Example 114 to givebenzyl-ethyl-sulfamic acid5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. MS (ESI) m/z456.0 (M+H)⁺

(d) Benzyl-ethyl-sulfamic acid5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

Benzyl-ethyl-sulfamic acid5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester is processedaccording to the method described in Example 128 to givebenzyl-ethyl-sulfamic acid5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. ¹H NMR(400 MHz, MeOD) δ ppm 1.15 (t, J=7.2 Hz, 3H), 3.43 (q, J=7.1 Hz, 2H),3.82 (s, 3H), 4.61 (s, 2H), 7.27-7.47 (m, 6H), 7.73 (d, J=8.6 Hz, 1H),7.77 (d, J=1.5 Hz, 1H), 8.06 (t, J=2.5 Hz, 1H), 8.72 (d, J=2.5 Hz, 1H),8.83 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 481.1085 [(M+H)⁺Calcd forC₂₄H₂₂ClN₄O₃S: 481.1101].

Example 160 (a) Morpholine-4-sulfonic acid 5-bromo-pyridin-3-yl ester

A flask is charged with 5-bromo-pyridin-3-ol (0.310 g, 1.78 mmol),potassium phosphate (0.982 g, 4.63 mmol) and acetone (10 mL), andmorpholine-4-sulfonyl chloride (0.529 g, 2.85 mmol) is added dropwise at0° C. The mixture is stirred at room temperature overnight. SaturatedNaHCO₃ in water (1 mL) is added and the mixture is concentrated invacuo. The residue is purified on silica gel chromatography eluting witha 9:1 to 4:1 heptane-ethyl acetate gradient to givemorpholine-4-sulfonic acid 5-bromo-pyridin-3-yl ester. MS (ESI) m/z322.9 and 324.9 (M+H)⁺.

(b) Morpholine-4-sulfonic acid 5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylester

Morpholine-4-sulfonic acid 5-bromo-pyridin-3-yl ester andN-methyl-indoleboronic acid are processed according to the methoddescribed in Example 100 to give morpholine-4-sulfonic acid5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. MS (ESI) m/z 374.1 (M+H)⁺

(c) Morpholine-4-sulfonic acid5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

Morpholine-4-sulfonic acid 5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl esteris processed according to the method described in Example 128 to givemorpholine-4-sulfonic acid5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.38-3.43 (m, 4H), 3.66-3.70 (m, 4H), 3.81 (s, 3H),7.34-7.39 (m, 1H), 7.42-7.48 (m, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.78 (d,J=8.3 Hz, 1H), 8.26 (dd, J=2.5, 2.0 Hz, 1H), 8.86 (d, J=2.5 Hz, 1H),8.90 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 399.1124 [(M+H)⁺ Calcd forC₁₉H₁₉N₄O₄S: 399.1127].

Example 161 (a) 4-Methyl-piperazine-1-sulfonic acid 5-bromo-pyridin-3-ylester

4-Methyl-piperazine-1-sulfonyl chloride is processed according to themethod described in Example 160a to give 4-methyl-piperazine-1-sulfonicacid 5-bromo-pyridin-3-yl ester. MS (ESI) m/z 335.9 and 337.9 (M+H)⁺.

(b) 4-Methyl-piperazine-1-sulfonic acid5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

4-Methyl-piperazine-1-sulfonic acid 5-bromo-pyridin-3-yl ester andN-methyl-indoleboronic acid are processed according to the methoddescribed in Example 100 to give 4-Methyl-piperazine-1-sulfonic acid5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. MS (ESI) m/z 387.1(M+H)⁺.

(c) 4-Methyl-piperazine-1-sulfonic acid5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

4-Methyl-piperazine-1-sulfonic acid5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester is processed according tothe method described in Example 128 to give4-methyl-piperazine-1-sulfonic acid5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.21 (s, 3H), 2.38-2.43 (m, 4H), 3.38-3.43 (m, 4H), 3.81(s, 3H), 7.34-7.39 (m, 1H), 7.42-7.48 (m, 1H), 7.73 (d, J=7.8 Hz, 1H),7.78 (d, J=8.3 Hz, 1H), 8.24 (dd, J=2.5, 1.8 Hz, 1H), 8.84 (d, J=2.5 Hz,1H), 8.90 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 412.1443 [(M+H)⁺Calcd forC₂₀H₂₂N₆O₃S: 412.1443].

Example 162 (a)6-Chloro-2-[5-(pyrrolidine-1-sulfonyloxy)-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester

1-Pyrrolidine-sulfonyl chloride and6-chloro-2-(5-hydroxy-pyridin-3-yl)-indole-1-carboxylic acid tert-butylester (Example 160a) are processed according to the method described inExample 160b to give6-chloro-2-[5-(pyrrolidine-1-sulfonyloxy)-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester, which is taken onto the next step without furtherpurification. MS (ESI) m/z 478.1 (M+H)⁺.

(b) Pyrrolidine-1-sulfonic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-ylester

6-Chloro-2-[5-(pyrrolidine-1-sulfonyloxy)-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester is dissolved in DCM (2 mL), and the mixture iscooled to 0° C. TFA (2 mL) is added and the mixture is stirred at roomtemperature for 1 h. Saturated sodium bicarbonate is then added and themixture is extracted with DCM. The organic layer is dried over sodiumsulfate and concentrated in vacuo to afford pyrrolidine-1-sulfonic acid5-(6-chloro-1H-indol-2-yl)-pyridin-3-yl ester as an oil which is takenonto the next step without further purification. MS (ESI) m/z 376.2(M+H)⁺.

(c) Pyrrolidine-1-sulfonic acid5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

Pyrrolidine-1-sulfonic acid 5-(6-chloro-1H-indol-2-yl)-pyridin-3-ylester is processed according to the method described in Example 109 togive pyrrolidine-1-sulfonic acid5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. MS (ESI) m/z392.0 (M+H)⁺.

(d) Pyrrolidine-1-sulfonic acid5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester

Pyrrolidine-1-sulfonic acid5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester is processedaccording to the method described in Example 128 to givepyrrolidine-1-sulfonic acid5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. ¹H NMR(400 MHz, MeOD) δ ppm 2.01-2.09 (m, 4H), 3.53-3.60 (m, 4H), 3.85 (s,3H), 7.39 (dd, J=8.3, 1.8 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.79 (d,J=1.5 Hz, 1H), 8.17 (dd, J=2.5, 1.8 Hz, 1H), 8.81 (d, J=2.5 Hz, 1H),8.85 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 417.0788 [(M+H)⁺Calcd forC₁₉H₁₉N₄O₃SCl: 417.0788].

Example 163 (a) N-(5-Bromo-pyridin-3-ylmethyl)-methanesulfonamide

To a solution of 5-bromo-3-pyridine-carboxaldehyde (1.5 g, 7.9 mmol),methanesulfonamide (0.5 g, 5.3 mmol), acetic acid (0.637 g, 10.6 mmol),triethylamine (1.07 g, 10.6 mmol) in DCE (50 mL) at ambient temperatureis added NaBH(OAc)₃ (3.14 g, 14.84 mmol). The reaction mixture isstirred overnight. Aqueous NaHCO₃ (20 mL) is added and the organic phaseis separated. The aqueous phase is extracted with dichloromethane andthe combined organic phase is dried over Na₂SO₄. Concentration affords aresidue which is purified by silica gel flash chromatography with amethanol in dichloromethane gradient to affordN-(5-bromo-pyridin-3-ylmethyl)-methanesulfonamide as a solid. MS (ESI)m/z 266.9 (M+H)⁺.

(b) N-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide

N-(5-Bromo-pyridin-3-ylmethyl)-methanesulfonamide andN-methyl-indoleboronic acid are processed according to the methoddescribed in Example 100 to giveN-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide. ¹HNMR (400 MHz, MeOD) δ ppm 3.03 (s, 3H), 3.82 (s, 3H), 4.45 (s, 2H), 6.70(s, 1H), 7.13 (t, J=7.5 Hz, 1 H), 7.23-7.31 (m, 1H), 7.48 (d, J=8.1 Hz,1H), 7.63 (d, J=7.8 Hz, 1H), 8.10 (t, J=2.0 Hz, 1H), 8.62 (d, J=2.0 Hz,1H), 8.72 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 316.1108 [(M+H)⁺Calcd forC₁₆H₁₈N₃O₂S: 316.1120].

Example 164N-Methyl-N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide

N-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide(Example 163) is processed according to the method described in Example114 to giveN-methyl-N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.77 (s, 3H), 3.02 (s, 3H), 3.78 (s,3H), 4.41 (s, 2H), 6.72 (s, 1H), 7.07-7.13 (m, 1H), 7.20-7.25 (m, 1H),7.54 (d, J=8.3 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.95 (t, J=2.0 Hz, 1H),8.60 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H). MS (ESI) m/z 330.1(M+H)⁺.

Example 165N-Methyl-N-[5-(1-methyl-3-cyano-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide

N-Methyl-N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide(Example 164) is processed according to the method described in Example128 to giveN-methyl-N-[5-(1-methyl-3-cyano-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.80 (s, 3H), 3.03 (s, 3H), 3.82 (s,3H), 4.46 (s, 2H), 7.34-7.39 (m, 1H), 7.42-7.47 (m, 1H), 7.72 (d, J=7.8Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 8.09 (t, J=2.1 Hz, 1H), 8.77 (d, J=2.0Hz, 1H), 8.87 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 355.1229 [(M+H)⁺ Calcdfor C₁₈H₁₉N₄O₂S: 355.1229].

Example 166 (a)6-Chloro-2-[5-(methanesulfonyl-amino-methyl)-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester

A flask is charged withN-(5-bromo-pyridin-3-ylmethyl)-methanesulfonamide (Example 163a, 530 mg,2 mmol), N-Boc-6-chloro-indole-2-boronic acid (525 mg, 3.0 mmol), s-Phos(41 mg, 0.10 mmol), finely crushed potassium phosphate (849 mg, 4.0mmol) and toluene (20 mL), and the mixture is degassed for 15 min. Pd₂dba₃ (37 mg, 0.04 mmol) is added and the mixture is stirred at 85° C.for 1 h. The mixture is cooled to room temperature, diluted with DCM andsilica gel (10 g) is added. The mixture is concentrated in vacuo and theresidue is purified by silica gel flash chromatography eluting with a 0to 90% ethyl acetate-heptane gradient to give6-chloro-2-[5-(methanesulfonylamino-methyl)-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester. MS (ESI) m/z 436.1 and 437.9 (M+H)⁺.

(b)6-Chloro-2-[5-(methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester

To a solution of6-chloro-2-[5-(methanesulfonylamino-methyl)-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (530 mg, 1.22 mmol) in acetonitrile (10 mL) areadded Boc₂O (398 mg, 1.82 mmol) and DMAP (15 mg, 0.12 mmol). The mixtureis stirred for 1 h. Silica gel (1 g) is added and the mixture isconcentrated in vacuo. The residue is purified by silica gelchromatography to give6-chloro-2-[5-(methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester. MS (ESI) m/z 536.2 and 538.1 (M+H)⁺.

(c) N-[5-(6-Chloro-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide

A flask is charged with6-chloro-2-[5-(methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-indole-1-carboxylicacid tert-butyl ester (0.52 g, 0.97 mmol) and TFA (5 mL) and the mixtureis stirred at room temperature for 1 h. The mixture is concentrated invacuo to giveN-[5-(6-chloro-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamidewhich is used in the next step without further purification. MS (ESI)m/z 336.0 and 337.9 (M+H)⁺.

(d)N-[5-(6-Chloro-1H-indol-2-yl)-pyridin-3-ylmethyl]-N-methyl-methanesulfonamide

A flask is charged withN-[5-(6-chloro-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide(670 mg, 1.49 mmol), DMF (10 mL), dimethyl carbonate (403 mg, 4.47 mmol)and potassium carbonate (319 mg, 2.31 mmol), and the mixture is stirredat 150° C. for 5 h. The mixture is cooled to room temperature andpurified using Xbridge C18 eluting with a 1:9 to 9:1 acetonitrile-watergradient to giveN-[5-(6-chloro-1H-indol-2-yl)-pyridin-3-ylmethyl]-N-methyl-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.74 (s, 3H), 3.02 (s, 3H), 4.35 (s,2H), 7.04 (dd, J=8.5, 1.9 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 7.43 (d,J=1.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 8.14 (t, J=2.1 Hz, 1H), 8.47 (d,J=2.0 Hz, 1H), 9.05 (d, J=2.3 Hz, 1H), 11.92 (s, 1H). HRMS (ESI) m/z350.0738 [(M+H)⁺Calcd for C₁₆H₁₇ClN₃O₂S: 350.0730].

Example 167

N-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-N-methyl-methanesulfonamide

The method described in Example 166d also generatesN-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-N-methyl-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.78 (s, 3H), 3.02 (s, 3H), 3.77 (s,3H), 4.41 (s, 2H), 6.76 (d, J=0.8 Hz, 1H), 7.11 (dd, J=8.5, 1.9 Hz, 1H),7.62 (d, J=8.5 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.96 (t, J=2.2 Hz, 1H),8.62 (d, J=2.2 Hz, 1H), 8.78 (d, J=2.2 Hz, 1H). MS (ESI) m/z 364.1(M+H)⁺.

Example 168N-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-N-methyl-methanesulfonamide

N-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-N-methyl-methanesulfonamide(Example 167) is processed according to the method described in Example128 to giveN-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-N-methyl-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.78 (s, 3H), 3.02 (s, 3H), 3.79 (s,3H), 4.45 (s, 2H), 7.37 (dd, J=8.5, 1.9 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H),7.97 (d, J=1.5 Hz, 1H), 8.08 (t, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H),8.85 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 389.0835 [(M+H)⁺Calcd forC₁₈H₁₈ClN₄O₂S: 389.0839].

Example 169 (a)2-[5-(Methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-1-methyl-indole

To a solution ofN-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide(Example 163b) (337 mg, 0.200 mmol) in acetonitrile (5 mL) are addedBoc₂O (293 mg, 1.34 mmol) and DMAP (14 mg, 0.11 mmol). The reactionmixture is stirred for 1 h and after removal of the solvent, the residueis purified by silica gel flash chromatography to afford2-[5-(methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-1-methyl-indole.MS (ESI) m/z 416.2 (M+H)⁺.

(b)2-[5-(Methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-1-methyl-3-cyano-indole

To a solution of2-[5-(methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-1-methyl-indole(350 mg, 0.842 mmol) in dichloromethane (10 mL) is added chlorosulfonylisocyanate (0.358 g, 2.53 mmol). The mixture is stirred at ambienttemperature for 20 min, whereupon anhydrous DMF (2 mL) is added. After 1h, the mixture is concentrated to a volume of 3 mL, and filtered.Purification by RP HPLC affords2-[5-(methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-1-methyl-3-cyano-indole.MS (ESI) m/z 441.1 (M+H)⁺.

(c)N-[5-(3-Cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide

2-[5-(Methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-1-methyl-3-cyano-indole(260 mg, 0.59 mmol) in TFA (3 mL) at ambient temperature is stirred for30 min. The solvent is then removed in vacuo and the residue is purifiedby RP HPLC. The fractions containing the product are pooled andconcentrated and the residue is further purified by flash silica gelflash chromatography (methanol-dichloromethane gradient) to giveN-[5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.97 (s, 3H), 3.79 (s, 3H), 4.36 (br.s., 2H), 7.33-7.39 (m, 1H), 7.40-7.46 (m, 1H), 7.69-7.79 (m, 3H), 8.10(t, J=2.1 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H). HRMS(ESI) m/z 341.1068 [(M+H)⁺Calcd for C₁₇H₁₇N₄O₂S: 341.1072].

Example 170N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126, 50 mg, 0.169 mmol) and methanesulfonamide (24 mg, 0.254mmol), acetic acid (20 mg, 0.338 mmol), triethylamine (34 mg, 0.338mmol) in DCE (10 mL) are stirred for 30 min at ambient temperaturebefore adding NaBH(OAc)₃ (100 mg, 0.473 mmol). The reaction mixture isstirred overnight. NaHCO₃ (1 mL) is added and the solvents are removedin vacuo. The residue is purified using a Sunfire C18 with a gradient ofacetonitrile in 0.1% aqueous TFA and further purified with an XbridgeC18 using a gradient of acetonitrile in 0.1% NH₄OH to giveN-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamideas a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.97 (s, 3H), 3.78 (s, 3H),4.36 (s, 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.75(br. s., 1H), 7.97 (d, J=1.8 Hz, 1H), 8.10 (t, J=2.1 Hz, 1H), 8.78 (d,J=2.0 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 375.0681 [(M+H)⁺Calcd for C₁₇H₁₆ClN₄O₂S: 375.0682].

Example 171N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126b, 2.0 g, 6.09 mmol), ethanesulfonamide (1.33 g, 12.17 mmol)and toluene (250 mL), and titanium(IV) isopropoxide (2.59 g, 9.13 mmol)is added dropwise. The mixture is stirred at 120° C. overnight. Themixture is then concentrated in vacuo. The residue is taken up in DCM(150 mL) and MeOH (150 mL), and NaBH₄ (0.461 g, 12.17 mmol) is added at0° C. The mixture is stirred at 0° C. for 30 min. Water (50 mL) is addedand the mixture is stirred for 5 min. The suspension is filtered througha pad of celite. The celite layer is washed with DCM (3×50 mL). Thecombined organic phase is dried over Na₂SO₄ and concentrated to give aresidue is purified by silica gel flash chromatography (ethyl acetate).The resulting fractions containing the product are concentrated andrepurified by silica gel flash chromatography (dichloromethane-methanol,1:0 to 97:3). The concentrated product is redissolved in MeOH (500 mL)at 60° C. and concentrated in vacuo to giveN-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J=7.3 Hz, 3H), 3.06 (q, J=7.3Hz, 2H), 3.78 (s, 3H), 4.34 (d, J=6.3 Hz, 2H), 7.37 (dd, J=8.6, 1.8 Hz,1H), 7.73 (d, J=8.3 Hz, 1H), 7.77 (t, J=6.2 Hz, 1H), 7.97 (d, J=1.8 Hz,1H), 8.09 (t, J=2.1 Hz, 1H), 8.78 (d, J=1.8 Hz, 1H), 8.80 (d, J=1.8 Hz,1H). HRMS (ESI) m/z 389.0853 [(M+H)⁺Calcd for C₁₈H₁₇ClN₄O₂S: 389.0839].

Example 172N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-C,C,C-trifluoromethanesulfonamide

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and trifluoromethanesulfonamide are processed according tothe method described in Example 170 to giveN-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-C,C,C-trifluoromethanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.78 (s, 3H), 4.56 (s, 2H), 7.37 (dd,J=8.5, 1.9 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 8.09(t, J=2.1 Hz, 1H), 8.78 (d, J=2.3 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 10.16(br. s., 1H). HRMS (ESI) m/z 429.0412 [(M+H)⁺Calcd for C₁₇H₁₃ClF₃N₄O₂S:429.0400].

Example 173 2-Methyl-propane-2-sulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and 2-methyl-propane-2-sulfonic acid amide are processedaccording to the method described in Example 170 to give2-methyl-propane-2-sulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (s, 9H), 3.78 (s, 3H), 4.43 (d,J=6.1 Hz, 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.65 (t, J=6.2 Hz, 1H),7.73 (d, J=8.3 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 8.06 (t, J=2.1 Hz, 1H),8.77 (d, J=1.8 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 417.1150[(M+H)⁺ Calcd for C₂₀H₂₁ClN₄O₂S: 417.1152].

Example 174N-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-C-phenyl-methanesulfonamide

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and phenyl-methanesulfonamide are processed according tothe method described in Example 170 to giveN-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-C-phenyl-methanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.77 (s, 3H), 4.31 (s, 2H), 4.44 (s,2H), 7.30-7.41 (m, 6H), 7.73 (d, J=8.3 Hz, 1H), 7.83 (br. s., 1H), 7.97(d, J=1.5 Hz, 1H), 8.03 (t, J=2.1 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.79(d, J=2.0 Hz, 1H). HRMS (ESI) m/z 451.1006 [(M+H)⁺Calcd forC₂₃H₂₀ClN₄O₂S: 451.0996].

Example 175N-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-4-fluoro-benzenesulfonamide

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and 4-fluoro-benzenesulfonamide are processed according tothe method described in Example 170 to giveN-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-4-fluoro-benzenesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.74 (s, 3H), 4.23 (s, 2H), 7.33-7.41(m, 3H), 7.72 (d, J=8.6 Hz, 1H), 7.82-7.88 (m, 2H), 7.95 (d, J=1.5 Hz,2H), 8.44 (s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H). HRMS(ESI) m/z 455.0746 [(M+H)⁺Calcd for C₂₂H₁₇ClFN₄O₂S: 455.0745].

Example 1766-Chloro-2-[5-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and thiomorpholine-1,1-dioxide are processed according tothe method described in Example 170 to give6-chloro-2-[5-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.93-2.98 (m, 4H), 3.12-3.18 (m, 4H),3.81 (s, 3H), 3.87 (s, 2H), 7.37 (dd, J=8.5, 1.9 Hz, 1H), 7.73 (d, J=8.3Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 8.13 (t, J=2.0 Hz, 1H), 8.75 (d, J=2.0Hz, 1H), 8.81 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 415.1015 [(M+H)⁺Calcdfor C₂₀H₂₀ClN₄O₂S: 415.0996].

Example 1776-Chloro-2-{5-[(2-hydroxy-ethylamino)-methyl]-pyridin-3-yl}-1-methyl-1H-indole-3-carbonitrile

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and 2-amino-ethanol are processed according to the methoddescribed in Example 170 to give6-chloro-2-{5-[(2-hydroxy-ethylamino)-methyl]-pyridin-3-yl}-1-methyl-1H-indole-3-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.65-2.72 (m, 2H), 3.49-3.55 (m, 2H),3.79 (s, 3H), 3.92-3.98 (m, 2H), 4.61 (br. s., 1H), 7.37 (dd, J=8.3, 1.8Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 8.10-8.13 (m,1H), 8.75-8.79 (m, 2H). HRMS (ESI) m/z 341.1175 [(M+H)⁺Calcd forC₁₉H₁₈ClN₄O: 341.1169].

Example 178 (a){(R)-1-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester areprocessed according to the method described in Example 170 to give{(R)-1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester. MS (ESI) m/z 466.17 (M+H)⁺.

(b)2-[5-((R)-3-Amino-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile

To a solution of{(R)-1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester (140 mg, 0.3 mmol) in dichloromethane (5 mL) isadded TFA (2 mL) and the mixture is stirred at room temperature for 2 h.The solvents are then removed in vacuo and the residue is purified byXbridge C18 with a gradient of acetonitrile in 0.1% NH₄OH to give2-[5-((R)-3-amino-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.43 (m, 1H), 1.64 (br. s., 2H),1.97-2.08 (m, 1H), 2.21 (dd, J=9.0, 4.9 Hz, 1H), 2.59-2.68 (m, 1H), 2.71(dd, J=9.1, 6.6 Hz, 1H), 3.32-3.39 (m, 1H), 3.72 (q, J=13.6 Hz, 2H),3.79 (s, 3H), 7.36 (dd, J=8.3, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.96(d, J=1.5 Hz, 1H), 8.05 (t, J=2.0 Hz, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.77(d, J=2.3 Hz, 1H). HRMS (ESI) m/z 366.1483 [(M+H)⁺Calcd for C₂₀H₂₁ClN₅:366.1485].

Example 1796-Chloro-1-methyl-2-{5-[(2-pyrrolidin-1-yl-ethylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrile

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and 2-pyrrolidin-1-yl-ethylamine are processed accordingto the method described in Example 170 to give6-chloro-1-methyl-2-{5-[(2-pyrrolidin-1-yl-ethylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrile.The free base is taken up in 4M HCl in dioxane, concentrated in vacuo,dissolved in water and lyophilized to give the HCl salt. ¹H NMR (400MHz, DMSO-d₆) δ ppm (HCl salt) 1.83-1.93 (m, 2H), 2.04 (br. s., 2H),3.06 (br. s., 2H), 3.50 (br. s., 2H), 3.54-3.60 (m, 2H), 3.66 (br. s.,2H), 3.84 (s, 3H), 4.43 (br. s., 2H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 7.75(d, J=8.3 Hz, 1H), 8.01 (d, J=1.5 Hz, 1H), 8.43 (t, J=2.0 Hz, 1H), 8.94(d, J=2.0 Hz, 1H), 8.99 (d, J=2.0 Hz, 1H), 9.97 (br. s., 2H), 10.89 (br.s., 1H). HRMS (ESI) m/z 394.1803 [(M+H)⁺Calcd for C₂₂H₂₅ClN₅: 394.1798].

Example 1806-Chloro-2-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and 1-methanesulfonyl-piperazine are processed accordingto the method described in Example 170 to give6-chloro-2-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.55 (t, J=4.5 Hz, 4H), 3.14 (t, J=4.5Hz, 4H), 3.30 (s, 3H), 3.72 (s, 2H), 3.80 (s, 3H), 7.36 (dd, J=8.5, 1.9Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 8.06 (t, J=2.0Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z444.1265 [(M+H)⁺ Calcd for C₂₂H₂₅ClN₅: 444.1261].

Example 181 (a){1-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and piperidin-4-yl-carbamic acid tert-butyl ester areprocessed according to the method described in Example 170 to give{1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester. MS (ESI) m/z 480.1 (M+H)⁺.

(b)2-[5-(4-Amino-piperidin-1-ylmethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile

{1-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-piperidin-4-yl}-carbamicacid tert-butyl ester is processed according to the method described inExample 178b to give2-[5-(4-amino-piperidin-1-ylmethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm (trifluoroacetate salt) 1.75 (br. s.,2H), 2.07 (s, 3H), 3.08 (br. s., 2H), 3.54 (br. s., 2H), 3.84 (s, 3H),4.47 (br. s., 2H), 7.39 (dd, J=8.3, 1.8 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H),8.01 (d, J=1.5 Hz, 1H), 8.09 (br. s., 3H), 8.27 (s, 1H), 8.89 (s, 1H),9.01 (s, 1H), 10.11 (br. s., 1H). HRMS (ESI) m/z 380.1630 [(M+H)⁺Calcdfor C₂₁H₂₃ClN₅: 380.1642].

Example 182 (a)(S)-3-{[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butylester are processed according to the method described in Example 170 togive(S)-3-{[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester. MS (ESI) m/z 466.1 (M+H)⁺.

(b)6-Chloro-1-methyl-2-[5-((S)-pyrrolidin-3-ylaminomethyl)-pyridin-3-yl]-1H-indole-3-carbonitrile

(S)-3-{[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester is processed according to the method described inExample 178b to give6-chloro-1-methyl-2-[5-((S)-pyrrolidin-3-ylaminomethyl)-pyridin-3-yl]-1H-indole-3-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.50-1.59 (m, 1H), 1.77-1.88 (m, 1H),2.64-2.69 (m, 1H), 2.72-2.79 (m, 1H), 2.84 (dd, J=11.2, 5.9 Hz, 1H),2.88-2.96 (m, 1H), 3.13-3.20 (m, 1H), 3.31 (br. s., 2H), 3.79 (s, 3H),3.82 (s, 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.97(d, J=1.5 Hz, 1H), 8.09 (t, J=2.1 Hz, 1H), 8.73-8.77 (m, 2H). HRMS (ESI)m/z 366.1495 [(M+H)⁺Calcd for C₂₀H₂₁ClN₅: 366.1485].

Example 1836-Chloro-1-methyl-2-[5-(4-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole-3-carbonitrile

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and 1-methyl-piperazin-2-one are processed according tothe method described in Example 170 to give6-chloro-1-methyl-2-[5-(4-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-3-yl]-1H-indole-3-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.70 (br. s., 2H), 2.82 (s, 3H), 3.09(s, 2H), 3.29 (dd, J=11.0, 5.4 Hz, 2H), 3.73 (s, 2H), 3.80 (s, 3H), 7.36(dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H),8.09 (s, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H). HRMS (ESI)m/z 394.1437 [(M+H)⁺Calcd for C₂₁H₂₁ClN₅O: 394.1435].

Example 184 (a)(R)-3-{[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amino}-pyrrolidine-1-carboxylicacid tent-butyl ester

6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126) and (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butylester are processed according to the method described in Example 170 togive(R)-3-{[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester. MS (ESI) m/z 466.11 (M+H)⁺.

(b)6-Chloro-1-methyl-2-[5-((R)-pyrrolidin-3-ylaminomethyl)-pyridin-3-yl]-1H-indole-3-carbonitrile

(R)-3-{[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester is processed according to the method described inExample 178b to give6-chloro-1-methyl-2-[5-((R)-pyrrolidin-3-ylaminomethyl)-pyridin-3-yl]-1H-indole-3-carbonitrile.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52-1.61 (m, 1H), 1.79-1.88 (m, 1H),2.70 (dd, J=11.2, 3.9 Hz, 1H), 2.75-2.82 (m, 1H), 2.86 (dd, J=11.1, 5.8Hz, 1H), 2.90-2.98 (m, 1H), 3.14-3.21 (m, 1H), 3.39 (br. s., 2H), 3.79(s, 3H), 3.83 (s, 2H), 7.37 (dd, J=8.3, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz,1H), 7.96 (d, J=1.5 Hz, 1H), 8.10 (t, J=2.1 Hz, 1H), 8.74-8.77 (m, 2H).HRMS (ESI) m/z 366.1486 [(M+H)⁺Calcd for C₂₀H₂₁ClN₅ 366.1485].

Example 1856-Chloro-1-methyl-2-{5-[(1-methyl-piperidin-4-ylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrile

To a solution of6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 126, 0.150 g, 0.482 mmol) in THF (3 mL) and DMF (1 mL) is added4-amino-1-methylpiperidine (0.067 g, 0.578 mmol), followed withMP-NaBH₃CN (2.42 mmol/g, 0.498 g, 1.205 mmol). After 16 h, MP-NaBH₃CN(2.42 mmol/g, 0.200 g, 0.484 mmol) is added. After another 46 h andPL-benzaldehyde (1.8 mmol/g, 0.268 g, 0.482 mmol) is added and afteranother 8 h, the mixture is filtered and the solids are washed with THF.After evaporation of the solvents, the residue is purified by reversephase H PLC on a Sunfire C18, eluting with a gradient of 0.1% aqueousTFA-acetonitrile to give6-chloro-1-methyl-2-{5-[(1-methyl-piperidin-4-ylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrileas a gum which is triturated with 1M HCl in ether to give the HCl salt.¹H NMR (400 MHz, DMSO-d₆) δ ppm (HCl salt) 1.46-1.66 (m, 2H), 1.93-2.04(m, 2H), 2.50-2.57 (m, 4H), 2.66-2.76 (m, 2H), 3.10-3.20 (m, 2H), 3.80(s, 3H), 3.95 (br. s., 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.6Hz, 1H), 7.98 (d, J=1.8 Hz, 1H), 8.16 (s, 1H), 8.79 (d, J=2.0 Hz, 1H),8.80 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 394.1804 [(M+H)⁺Calcd forC₂₂H₂₅ClN₅: 394.1798].

Example 186 (a) 2-(5-Bromo-pyridin-3-yl)-methanol

A flask is charged with 5-bromo-pyridine-3-carbaldehyde (5.0 g, 26.1mmol) and methanol (200 mL) and cooled to 0° C. Sodium borohydride (2.99g, 78.23 mmol) is added and the reaction is stirred at room temperaturefor 2 h. The solvent is removed in vacuo. The residue is redissolved indichloromethane and washed with water twice. The combined aqueous layeris saturated with sodium chloride and extracted with ethyl acetate. Thecombined organic layer is dried over sodium sulfate and concentrated invacuo to afford 2-(5-bromo-pyridin-3-yl)-methanol as a solid. MS (ESI)m/z 189.9 (M+H)⁺

(b) 2-(5-bromo-pyridin-3-ylmethyl)-isoindole-1,3-dione

A flask is charged with 2-(5-bromo-pyridin-3-yl)-methanol (4.70 g, 23.75mmol), phthalimide (3.92 g, 26.12 mmol), tributylphosphine (11.04 mL,44.527 mmol) and THF (50 mL). 1,1′-(Azodicarbonyl)dipiperidine (11.80 g,46.31 mmol) is added and the reaction is stirred at room temperature for6 h, diluted with ethyl acetate and washed with water thrice. Theorganic layer is dried over sodium sulfate and concentrated in vacuo togive a residue which is purified by silica gel flash chromatography(heptane-ethyl acetate, 1:1) to afford2-(5-bromo-pyridin-3-ylmethyl)-isoindole-1,3-dione as a solid. MS (ESI)m/z 319.1 (M+H)⁺.

(c)2-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isoindole-1,3-dione

6-Chloro-1-methyl-indole-2-boronic acid and2-(5-bromo-pyridin-3-ylmethyl)-isoindole-1,3-dione are processedaccording to the method described in Example 100 to give2-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]isoindole-1,3-dione.MS (ESI) m/z 402.1 (M+H)⁺.

(d)6-chloro-2-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile

2-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]isoindole-1,3-dioneis processed according to the method described in Example 128 to give6-chloro-2-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrileas a solid. MS (ESI) m/z 427.0 (M+H)⁺.

(e)2-(5-Aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile

To a solution of6-chloro-2-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile(8.96 g, 18.89 mmol) in ethanol (200 mL) is added hydrazine (12.10 mL,378 mmol) and the reaction mixture is stirred overnight. The mixture isthen filtered and the solids are washed with ethyl acetate. The filtrateis partially concentrated to remove ethyl acetate. 1M aqueous HCl isadded, and the aqueous mixture is washed with EtOAc. The aqueous layeris then basified with 4M aqueous NaOH and extracted with dichloromethanethrice. The dichloromethane extracts are dried over Na₂SO₄ andconcentrated in vacuo to afford2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrileas a solid. MS (ESI) m/z 297.0 (M+H)⁺

(f) Propane-2-sulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide

A flask is charged with2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(0.075 g, 0.253 mmol) and dichloromethane (2 mL). Isopropylsulfonylchloride (0.031 mL, 0.278 mmol) and triethylamine (0.071 mL, 0.506 mmol)are added and the reaction is stirred at room temperature overnight. Thereaction mixture is concentrated in vacuo. The residue is purified byreverse phase HPLC with Xbridge Shield RP18 column and a 0.1% aqueousNH₄OH in acetonitrile gradient to afford propane-2-sulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amideas a solid. ¹H NMR (400 MHz, MeOD) δ ppm 1.40 (d, J=6.8 Hz, 6H),3.25-3.32 (m, 1H), 3.84 (s, 3H), 4.50 (s, 2H), 7.38 (dd, J=8.6, 1.8 Hz,1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.18 (t, J=2.0 Hz,1H), 8.81 (t, J=1.9 Hz, 2H). HRMS (ESI) m/z 403.0997 [(M+H)⁺Calcd forC₁₉H₂₀ClN₄O₂S: 403.0996].

Example 187 2,2,2-Trifluoro-ethanesulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide

2-(5-Aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e) and 2,2,2-trifluoro-ethanesulfonyl chloride are processedaccording to the method described in Example 186f to give2,2,2-trifluoro-ethanesulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide.¹H NMR (400 MHz, MeOD) δ ppm 3.84 (s, 3H), 4.29 (q, J=9.6 Hz, 2H), 4.54(s, 2H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.78 (d,J=1.8 Hz, 1H), 8.18 (t, J=2.0 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.83 (d,J=2.0 Hz, 1H). HRMS (ESI) m/z 443.0557 [(M+H)⁺Calcd for C₁₈H₁₅N₄O₂F₃SCl:443.0556].

Example 188 (a) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonicacid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide

A flask is charged with2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e, 0.050 g, 0.160 mmol) and dichloromethane (2 mL).2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.068g, 0.239 mmol) and triethylamine (0.045 mL, 0.319 mmol) are added andthe reaction is stirred at room temperature for 5 min. The reactionmixture is washed with water and extracted with dichloromethane twice.The combined organic phase is separated, dried over sodium sulfate andconcentrated in vacuo to give a residue which is purified by silica gelflash chromatography (dichloromethane-methanol, 19:1) to afford2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethane sulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amideas a white solid. MS (ESI) m/z 537.3 (M+H)⁺.

(b) 2-Amino-ethanesulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide

A flask is charged with2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide(0.065 g, 0.109 mmol) and MeOH (4 mL). Hydrazine (0.069 mL, 2.183 mmol)is added and the reaction is stirred at room temperature overnight. 2Maqueous HCl is added, followed by concentration in vacuo.Dichloromethane is added and the mixture is filtered through celite. Theorganic layer is washed with water once and the aqueous layer isbasified to using 4M aqueous NaOH and extracted with dichloromethanethrice. The combined dichloromethane fraction is dried over sodiumsulfate and concentrated in vacuo to afford a residue which is purifiedby reverse-phase HPLC to afford 2-amino-ethanesulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amideas a solid. ¹H NMR (400 MHz, MeOD) δ ppm 3.12 (t, J=6.6 Hz, 2H), 3.29(t, J=6.6 Hz, 2H), 3.84 (s, 3H), 4.49 (s, 2H), 7.38 (dd, J=8.6, 1.8 Hz,1H), 7.73 (d, J=8.6 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H), 8.19 (t, J=2.1 Hz,1H), 8.81 (d, J=2.3 Hz, 1H), 8.82 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z404.0944 [(M+H)⁺Calcd for C₁₈H₁₉ClN₅O₂S: 404.0948].

Example 189N,N-diethyl-N′-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-sulfamide

A flask is charged with2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e, 0.103 g, 0.349 mmol) and dichloromethane (2 mL).Diethylaminosulfamoyl chloride (0.072 g, 0.419 mmol) and triethylamine(0.100 mL, 0.699 mmol) are added and the reaction is stirred at roomtemperature overnight. The reaction mixture is concentrated in vacuo andthe residue is purified by reverse phase HPLC with Xbridge Shield RP18column and a 0.1% aqueous NH₄OH in acetonitrile gradient to affordN,N-diethyl-N′-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-sulfamideas a solid. ¹H NMR (400 MHz, MeOD) δ ppm 1.20 (t, J=7.1 Hz, 6H), 3.30(q, J=7.1 Hz, 4H), 3.83 (s, 3H), 4.35 (s, 2H), 7.38 (dd, J=8.6, 1.8 Hz,1H), 7.71 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.17 (t, J=2.1 Hz,1H), 8.79 (dd, J=3.7, 2.1 Hz, 2H). HRMS (ESI) m/z 432.1278 [(M+H)⁺Calcdfor C₂₀H₂₃ClN₅O₂S: 432.1261].

Example 1905-(6-chloro-3-cyano-1H-indol-2-yl)-pyridin-3-ylmethyl]-carbamic acidethyl ester

A flask is charged with2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e, 0.100 g, 0.349 mmol) and dichloromethane (4 mL). Ethylchloroformate (0.055 g, 0.506 mmol) and triethylamine (0.100 mL, 0.675mmol) are added and the reaction is stirred at room temperature for 10min. The reaction mixture is concentrated in vacuo and the residue ispurified by reverse phase HPLC with Xbridge Shield RP18 column and a0.1% aqueous NH₄OH in acetonitrile gradient to afford5-(6-chloro-3-cyano-1H-indol-2-yl)-pyridin-3-ylmethyl]-carbamic acidethyl ester as a solid. ¹H NMR (400 MHz, MeOD) δ ppm 1.28 (t, J=7.1 Hz,3H), 3.83 (s, 3H), 4.15 (q, J=7.1 Hz, 2H), 4.48 (s, 2H), 7.37 (dd,J=8.6, 1.8 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 8.09(t, J=1.9 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H). HRMS(ESI) m/z 369.1125 [(M+H)⁺Calcd for C₁₉H₁₈ClN₄O₂: 369.1118].

Example 191[5-(6-chloro-3-cyano-1H-indol-2-yl)-pyridin-3-ylmethyl]-carbamic acidpropyl ester

2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e) and N-propyl chloroformate are processed according to themethod described in Example 190 to give[5-(6-chloro-3-cyano-1H-indol-2-yl)-pyridin-3-ylmethyl]-carbamic acidpropyl ester as a solid. ¹H NMR (400 MHz, MeOD) δ ppm 0.98 (t, J=7.3 Hz,3H), 1.58-1.74 (m, 2H), 3.83 (s, 3H), 4.06 (t, J=6.6 Hz, 2H), 4.49 (s,2H), 7.38 (dd, J=8.6, 1.77 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d,J=1.5 Hz, 1H), 8.09 (t, J=2.0 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.78 (d,J=2.0 Hz, 1H). HRMS (ESI) m/z 383.1260 [(M+H)⁺ Calcd for C₂₀H₂₀ClN₄O₂:383.1275].

Example 1925-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]carbamicacid 2-methoxy-ethyl ester

2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e) and 3-methoxy-ethyl chloroformate are processed accordingto the method described in Example 190 to give5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]carbamicacid 2-methoxy-ethyl ester as a solid. ¹H NMR (400 MHz, MeOD) δ ppm 3.37(s, 3H), 3.58-3.65 (m, 2H), 3.83 (s, 3H), 4.14-4.27 (m, 2H), 4.50 (s,2H), 7.38 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d,J=1.5 Hz, 1H), 8.10 (s, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz,1H). HRMS (ESI) m/z 399.1221 [(M+H)⁺ Calcd for C₂₀H₂₀ClN₄O₃: 399.1224].

Example 1935-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-carbamicacid isobutyl ester

2-(5-Aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e) and isobutyl chloroformate are processed according to themethod described in Example 190 to give5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-carbamicacid isobutyl ester. ¹H NMR (400 MHz, MeOD) δ ppm 0.97 (d, J=6.6 Hz,6H), 1.85-2.01 (m, 1H), 3.83 (s, 3H), 3.89 (d, J=6.6 Hz, 2H), 4.49 (s,2H), 7.38 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.77 (d,J=1.8 Hz, 1H), 8.09 (t, J=2.1 Hz, 1H), 8.74 (d, J=1.8 Hz, 1H), 8.78 (d,J=2.0 Hz, 1H). HRMS (ESI) m/z 397.1424 [(M+H)⁺ Calcd for C₂₁H₂₂ClN₄O₂:397.1431].

Example 1945-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-carbamicacid isopropyl ester

2-(5-Aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e) and isopropyl chloroformate are processed according tothe method described in Example 190 to give5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-carbamicacid isopropyl ester. ¹H NMR (400 MHz, MeOD) δ ppm 1.27 (d, J=6.3 Hz,6H), 3.83 (s, 3H), 4.48 (s, 2H), 4.88-4.94 (m, 1H), 7.38 (dd, J=8.6, 1.8Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.09 (t, J=1.9Hz, 1H), 8.73 (d, J=1.8 Hz, 1 H), 8.78 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z383.1266 [(M+H)⁺Calcd for C₂₀H₂₀ClN₄O₂: 383.1275].

Example 1951-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-3-ethyl-urea

To a solution of2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e, 0.100 g, 0.337 mmol) in dichloromethane (3 mL) is addedethyl isocyanate (0.030 g, 0.422 mmol) and the reaction is stirred atroom temperature for 45 min. The mixture is then washed with water andextracted with dichloromethane twice. The organic phase is concentratedin vacuo to give a residue which is purified by reverse phase HPLC withXbridge Shield RP18 column and a 0.1% aqueous NH₄OH in acetonitrilegradient to afford1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-3-ethyl-ureaas a solid. ¹H NMR (400 MHz, MeOD) δ ppm 1.14 (t, J=7.2 Hz, 3H), 3.20(q, J=7.3 Hz, 2H), 3.82 (s, 3H), 4.52 (s, 2H), 7.38 (dd, J=8.3, 1.8 Hz,1H), 7.71 (d, J=8.6 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 8.08 (t, J=2.1 Hz,1H), 8.73 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z368.1275 [(M+H)⁺ Calcd for C₁₉H₁₉ClN₅O: 368.1278].

Example 1961-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-3-isopropyl-urea

To a solution of2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e, 0.060 g, 0.192 mmol) in dichloromethane (3 mL) is addedisopropyl isocyanate (0.027 g, 0.240 mmol) and the reaction is stirredat room temperature for 45 min. The mixture is then washed with waterand extracted with dichloromethane twice. The organic phase isconcentrated in vacuo to give a residue which is redissolved inmethanol. A precipitate crashes out upon standing. The solid is filteredto afford1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-3-isopropyl-ureaas a solid. ¹H NMR (400 MHz, MeOD) δ ppm 1.17 (d, J=6.6 Hz, 6H),3.76-3.91 (m, 4H), 4.52 (s, 2H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 7.72 (d,J=8.3 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.08 (t, J=2.1 Hz, 1H), 8.73 (d,J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 382.1431[(M+H)⁺Calcd for C₂₀H₂₁N₅OCl: 382.1435].

Example 1971-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-3-cyclopentyl-urea

2-(5-Aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e) and cyclopentyl isocyanate are processed according to themethod described in Example 196 to give1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-3-cyclopentyl-ureaas a solid. ¹H NMR (400 MHz, MeOD) δ ppm 1.31-1.54 (m, 2H), 1.56-1.68(m, 2H), 1.68-1.78 (m, 2H), 1.86-2.13 (m, 2H), 3.83 (s, 3H), 3.94-4.09(m, 1H), 4.52 (s, 2H), 7.38 (dd, J=8.3, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz,1H), 7.77 (d, J=1.5 Hz, 1H), 8.08 (t, J=2.0 Hz, 1H), 8.72 (d, J=2.0 Hz,1H), 8.76 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 408.1591 [(M+H)⁺Calcd forC₂₂H₂₃N₅OCl: 408.1591].

Example 198 Morpholine-4-carboxylic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide

To a solution of2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e, 0.060 g, 0.202 mmol) in dichloromethane (2 mL) are addedmorpholine-4-carbonyl chloride (0.026 g, 0.222 mmol) and triethylamine(0.056 mL, 0.405 mmol) and the reaction is stirred at room temperatureovernight. The mixture is then washed with water and extracted withdichloromethane twice. The organic phase is dried over sodium sulfateand concentrated in vacuo. The residue is purified by silica gel flashchromatography (dichloromethane-methanol, 19:1) to affordmorpholine-4-carboxylic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amideas a solid. ¹H NMR (400 MHz, MeOD) δ ppm 3.41-3.47 (m, 4H), 3.66-3.72(m, 4H), 3.84 (s, 3H), 4.55 (s, 2H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 7.72(d, J=8.6 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 8.11 (t, J=2.1 Hz, 1H), 8.73(d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). MS (ESI) m/z 410.00 (M+H)⁺.

Example 199N-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-butyramide

To a solution of2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 186e, 0.060 g, 0.202 mmol) in dichloromethane (2 mL) is addedbutyryl chloride (0.024 g, 0.222 mmol) and triethylamine (0.056 mL,0.405 mmol), and the reaction is stirred at room temperature for 30 min.The reaction mixture is diluted with dichloromethane and washed withwater. The organic layer is dried over sodium sulfate and concentratedin vacuo. The residue is purified by silica gel flash chromatography(dichloromethane-methanol, 19:1) to affordN-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-butyramideas a white solid. ¹H NMR (400 MHz, MeOD) δ ppm 0.98 (t, J=7.5 Hz, 3H),1.65-1.77 (m, 2H), 2.29 (t, J=7.5 Hz, 2H), 3.82 (s, 3H), 4.57 (s, 2H),7.38 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.5 Hz,1H), 8.09 (t, J=2.1 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz,1H). HRMS (ESI) m/z 367.1327 [(M+H)⁺Calcd for C₂₀H₂₀N₄OCl: 367.1326].

Example 200 (a)2-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isoindole-1,3-dione

2-(5-Bromo-pyridin-3-ylmethyl)-isoindole-1,3-dione (Example 186b) and1-methyl-indole-2-boronic acid are processed according to the methoddescribed in Example 100 to give2-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isoindole-1,3-dione asa solid. MS (ESI) m/z 368.09 (M+H)⁺.

(b) C-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine

2-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isoindole-1,3-dione isprocessed according to the method described in Example 186e to giveC-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine as a solid. MS(ESI) m/z 238.06 (M+H)⁺.

Example 201N-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]ethanesulfonamide

C-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 200b)and ethanesulfonyl chloride are processed according to the methoddescribed in Example 186f to giveN-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide. ¹HNMR (400 MHz, MeOD) δ ppm 1.37 (t, J=7.3 Hz, 3H), 3.13 (q, J=7.4 Hz,2H), 3.82 (s, 3H), 4.43 (s, 2H), 6.70 (s, 1H), 7.01-7.18 (m, 1H),7.20-7.36 (m, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 8.10(t, J=2.1 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H). HRMS(ESI) m/z 330.1288 [(M+H)⁺Calcd for C₁₇H₂₀N₃O₂S: 330.1276].

Example 202N-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isopropylsulfonamide

C-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 200b)and isopropylsulfonyl chloride are processed according to the methoddescribed in Example 186f to giveN-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isopropylsulfonamide.¹H NMR (400 MHz, MeOD) δ ppm 1.40 (d, J=6.82 Hz, 6H), 3.23-3.32 (m, 1H),3.83 (s, 3H), 4.45 (s, 2H), 6.70 (s, 1H), 7.09-7.17 (m, 1H), 7.27 (ddd,J=7.6, 1.14 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H),8.11 (t, J=2.1 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H).HRMS (ESI) m/z 344.1431 [(M+H)⁺Calcd for C₁₈H₂₂N₃O₂S: 344.1433].

Example 203C,C,C-Trifluoro-N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide

C-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 200b)and trifluoromethanesulfonyl chloride are processed according to themethod described in Example 186f to give C, C,C-trifluoro-N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide.¹H NMR (400 MHz, MeOD) δ ppm 3.78 (s, 3H), 4.23 (q, J=9.6 Hz, 2H), 6.66(d, J=0.5 Hz, 1H), 7.04-7.13 (m, 1H), 7.23 (ddd, J=7.7, 1.1 Hz, 1H),7.44 (d, J=8.2 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 8.04 (t, J=2.0 Hz, 1H),8.56 (d, J=2.0 Hz, 1H), 8.68 (d, J=1.9 Hz, 1H). HRMS (ESI) m/z 370.0835[(M+H)⁺Calcd for C₁₆H₁₅F₃N₃O₂S: 370.0837].

Example 204 2,2,2-Trifluoro-ethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide

C-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 200b)and 2,2,2-trifluoro-ethanesulfonyl chloride are processed according tothe method described in Example 186f to give2,2,2-trifluoro-ethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. ¹H NMR (400 MHz,MeOD) δ ppm 3.78 (s, 3H), 4.23 (q, J=9.6 Hz, 2H), 4.44 (s, 2H), 6.66 (d,J=0.5 Hz, 1H), 7.06-7.12 (m, 1H), 7.23 (ddd, J=7.7, 1.1 Hz, 1H), 7.44(d, J=8.2 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 8.04 (t, J=2.0 Hz, 1H), 8.56(d, J=2.0 Hz, 1H), 8.68 (d, J=1.9 Hz, 1H). HRMS (ESI) m/z 384.0999[(M+H)⁺ Calcd for C₁₇H₁₇F₃N₃O₂S: 384.0994].

Example 205 (a)C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine

2-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]isoindole-1,3-dione(Example 186c) is processed according to the method described in Example186e to giveC-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine. MS(ESI) m/z 272.01 (M+H)⁺.

(b)N-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide

C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine andmethanesulfonyl chloride are processed according to the method describedin Example 186f to giveN-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide.¹H NMR (400 MHz, MeOD) δ ppm 3.03 (s, 3H), 3.80 (s, 3H), 4.45 (s, 2H),6.71 (s, 1H), 7.12 (dd, J=8.3, 1.8 Hz, 1H), 7.54 (s, 1H), 7.59 (d, J=8.6Hz, 1H), 8.09 (t, J=2.2 Hz, 1H), 8.63 (d, J=2. Hz, 1H), 8.71 (d, J=2.Hz, 1H). HRMS (ESI) m/z 350.0728 [(M+H)⁺Calcd for C₁₆H₁₇ClN₃O₂S:350.0730].

Example 206N-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide

A flask is charged with6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole (Example 126a, 1.2g, 4.43 mmol), ethanesulfonamide (0.726 g, 6.65 mmol), titanium(IV)isopropoxide (2.60 mL, 8.87 mmol) and toluene (50 mL). The reactionmixture is refluxed overnight and then concentrated to dryness. Thecrude material (1.60 g) is dissolved in MeOH (24 mL) and DCM (24 mL),and sodium borohydride (0.335 g, 8.87 mmol) is added. The reactionmixture is stirred at room temperature for 2 h, then concentrated invacuo. The residue is taken up in DCM and washed with water twice. Theorganic layer is dried over sodium sulfate, filtered and concentrated invacuo. Purification is achieved by silica gel flash chromatograpy togiveN-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide.¹H NMR (400 MHz, MeOD) δ ppm 1.38 (t, J=7.3 Hz, 3H), 3.14 (q, J=7.3 Hz,2H), 3.80 (s, 3H), 4.43 (s, 2H), 6.72 (s, 1H), 7.12 (dd, J=8.5, 1.9 Hz,1H), 7.54 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 8.10 (t, J=2.1 Hz,1H), 8.63 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z364.0869 [(M+H)⁺Calcd for C₁₇H₁₉ClN₃O₂S: 364.0887].

Example 207N-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]isopropylsulfonamide

C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine(Example 205a) and isopropylsulfonyl chloride are processed according tothe method described in Example 186f to giveN-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-isopropylsulfonamide.¹H NMR (400 MHz, MeOD) δ ppm 1.35 (d, J=6.8 Hz, 6H), 3.19-3.27 (m, 1H),3.76 (s, 3H), 4.40 (s, 2H), 6.67 (d, J=0.6 Hz, 1H), 7.07 (dd, J=8.4, 1.8Hz, 1H), 7.49 (d, J=1.6 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 8.06 (t, J=2.0Hz, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.66 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z378.1036 [(M+H)⁺Calcd for C₁₈H₂₁ClN₃O₂S: 378.1043].

Example 208C,C,C-Trifluoro-N-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide

C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine(Example 205a) and trifluoromethanesulfonyl chloride are processedaccording to the method described in Example 186f to giveC,C,C-trifluoro-N-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide.¹H NMR (400 MHz, MeOD) δ ppm 3.80 (s, 3H), 4.59 (s, 2H), 6.72 (s, 1H),7.12 (dd, J=8.5, 1.9 Hz, 1H), 7.54 (s, 1H), 7.60 (d, J=8.6 Hz, 1H), 8.05(t, J=2.1 Hz, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). HRMS(ESI) m/z 404.0443 [(M+H)⁺Calcd for C₁₆H₁₄ClF₃N₃O₂S: 404.0447].

Example 209 2,2,2-Trifluoro-ethanesulfonic acid[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide

C-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine(Example 205a) and 2,2,2-trifluoro-ethanesulfonyl chloride are processedaccording to the method described in Example 186f to give2,2,2-trifluoro-ethanesulfonic acid[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. ¹H NMR(400 MHz, MeOD) δ ppm 3.75 (d, J=0.6 Hz, 3H), 4.16-4.28 (m, 2H), 4.44(s, 2H), 6.67 (s, 1H), 7.07 (ddd, J=8.4, 1.8, 0.8 Hz, 1H), 7.50 (s, 1H),7.55 (d, J=8.3 Hz, 1H), 8.04 (d, J=0.6 Hz, 1H), 8.58 (d, J=1.4 Hz, 1 H),8.68 (d, J=1.6 Hz, 1H). HRMS (ESI) m/z 418.06107 [(M+H)⁺Calcd forC₁₇H₁₆N₃O₂F₃SCl: 418.06039].

Example 210 (a) Bis-ethanesulfonic acid (5-bromo-pyridin-3-yl)-amide

To a solution of 3-amino-5-bromo-pyridine (4.300 g, 23.611 mmol) indichloromethane (100 mL) is added ethanesulfonyl chloride (6.849 g,70.834 mmol), followed with di-isopropylethylamine (16.61 mL, 94.445mmol). The mixture is stirred at room temperature for 5 h, whereupon itis diluted with ethyl acetate and washed with water twice. The organiclayer is dried over sodium sulfate and concentrated in vacuo. Theresidue is purified by silica gel flash chromatography (heptane-ethylacetate, 3:2) to afford bis-ethanesulfonic acid(5-bromo-pyridin-3-yl)-amide as a solid. MS (ESI) m/z 359.0 (M+H)⁺.

(b) Ethanesulfonic acid 3-(6-chloro-1-methyl-1H-indol-2-yl)-benzylamide

A flask is charged with 6-chloro-1-methyl-indole-2-boronic acid (0.165g, 0.756 mmol), bis-ethanesulfonic acid (5-bromo-pyridin-3-yl)-amide(0.200 g, 0.504 mmol), potassium phosphate (0.221 g, 1.008 mmol) and DMF(5 mL). The flask is evacuated and back-filled with N₂ thrice andPd(PPh₃)₄ (0.029 g, 0.025 mmol) is added. The mixture evacuated andback-filled with N₂ thrice again, and stirred at 90° C. overnight. It isthen cooled to room temperature, diluted with ethyl acetate and washedwith water thrice. The organic layer is dried over sodium sulfate andconcentrated in vacuo. The residue is purified by silica gel flashchromatography (dichloromethane-methanol, 19:1) and further purified byreverse phase HPLC with Xbridge Shield RP18 column and a 0.1% aqueousNH₄OH in acetonitrile gradient to afford ethanesulfonic acid3-(6-chloro-1-methyl-1H-indol-2-yl)-benzylamide as a solid. ¹H NMR (400MHz, MeOD) δ ppm 1.40 (t, J=7.3 Hz, 3H), 3.24 (q, J=7.3 Hz, 2H), 3.80(s, 3H), 6.71 (s, 1H), 7.12 (dd, J=8.3, 1.8 Hz, 1H), 7.54 (s, 1H), 7.59(d, J=8.3 Hz, 1H), 7.92 (t, J=2.1 Hz, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.49(d, J=1.8 Hz, 1H). HRMS (ESI) m/z 350.0731 [(M+H)⁺Calcd forC₁₆H₁₇ClN₃O₂S: 350.0730].

Example 211 (a)3-[Bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-bromo-pyridine

To 5-amino-3-bromo-pyridine (1.73 g, 10 mmol) and Boc₂O (4.8 g, 22 mmol)in acetonitrile (100 mL) at ambient temperature is added DMAP (212 mg, 1mmol) and the reaction mixture is heated to 50° C. and stirredovernight. Boc₂O (2.2 g, 10 mmol) is added to the reaction mixture,which is stirred at 50° C. for another 4 h. The reaction mixture is thencooled to room temperature. The solvent is removed in vacuo and theresidue is purified by silica gel flash chromatography to afford3-[bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-bromo-pyridine as awhite solid. MS (ESI) m/z 374.9 (M+H)⁺.

(b)3-[Bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridine

A flask is charged with3-[bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-bromo-pyridine (1.12 g,3.0 mmol), N-methyl-6-chloroindole-2-boronic acid (754 mg, 3.6 mmol),finely crushed potassium phosphate (1.27 g, 6.0 mmol) and DMF (20 mL).After degassing for 15 min, Pd(PPh₃)₄ (173 mg, 0.15 mmol) is added. Theflask is flushed with nitrogen and the mixture is heated to 90° C. andstirred for 5 h. The mixture is then cooled to room temperature andpoured into water (100 mL). The mixture is extracted with EtOAc threetimes and the combined organic phase is washed with water (10 mL) twice.The organic phase is then dried over Na₂SO₄ and concentrated. Theresidue is purified by silica gel flash chromatography (ethylacetate-heptane, 0:1 to 1:9) to give3-[bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridine.MS (ESI) m/z 458.1 (M+H)⁺.

(c) 2-(5-Amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile

Chlorosulfonyl isocyanate (1.63 g, 11.5 mmol) is added to a solution of3-[bis[[(1,1-dimethylethyl)oxy]carbonyl]amino]-5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridine(0.91 g, 1.99 mmol) in acetonitrile (200 mL) and the reaction mixture isstirred for 10 min. DMF (3 mL) is added and the reaction mixture isstirred for 3 h. 20 g silica gel is added to the mixture and the solventis removed in vacuo. The resulting solid is heated to 65° C. under highvacuum for 2 h. The mixture is cooled to room temperature and thenpurified by silica gel flash chromatography(dichloromethane-methanol-triethylamine, 83:8:9) to afford2-(5-amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 3.76 (s, 3H), 5.72 (s, 2H), 7.15 (t, J=2.3Hz, 1H), 7.35 (dd, J=8.5, 1.9 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.92 (d,J=1.8 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 8.12 (d, J=2.5 Hz, 1H). MS (ESI)m/z 283.0 (M+H)⁺.

Example 212 Ethanesulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide

To a solution of2-(5-amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 211, 85 mg, 0.3 mmol) in DCM (15 mL) is added triethylamine(122 mg, 1.2 mmol) and ethanesulfonyl chloride (77 mg, 0.6 mmol) and thereaction mixture is stirred overnight. The solvent is removed and theresidue is redissolved in methanol (15 mL). Aqueous 1M NaOH (1 mL) isadded and the reaction mixture is stirred overnight. The solvent isremoved in vacuo and the residue is purified by silica gel flashchromatography (methanol in dichloromethane gradient) to giveethanesulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide as asolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (t, J=7.3 Hz, 3H), 3.23-3.33(m, 2H), 3.79 (s, 3H), 7.36 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz,1H), 7.90 (t, J=2.3 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 8.61 (d, J=2.3 Hz,2H), 10.43 (s, 1H). HRMS (ESI) m/z 375.0692 [(M+H)⁺Calcd forC₁₇H₁₆ClN₄O₂S: 375.0682].

Example 213 (a) 1-Formyl-cyclobutanecarboxylic acid ethyl ester

To a solution of diethyl 1,1′-cyclobutanedicarboxylate (9.9 g, 48.4mmol) in dichloromethane (100 mL) cooled with a dry-ice/acetone bath isadded DIBAL-H (20% wt in toluene, 101 mL, 121.1 mmol) by canula over 10min. The mixture is stirred for another 30 min, whereupon the acetonebath is replaced with an ice water bath and 2M aqueous HCl (250 mL) isadded cautiously, with vigorous stirring. Vigorous stirring is continuedfor 20 min, whereupon two clear phases are obtained. The two phases areseparated, the aqueous phase is washed with dichloromethane and thecombined organic phase is dried over MgSO₄, filtered and concentrated invacuo. The residue is purified by silica gel flash chromatography(heptane-ethyl acetate, 1:0 to 9:1) to give1-formyl-cyclobutanecarboxylic acid ethyl ester as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.29 (t, J=7.1 Hz, 3H), 1.88-2.05 (m, 2H),2.45-2.49 (m, 4H), 4.24 (t, J=7.1 Hz, 2H), 9.78 (s, 2H).

(b)1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylicacid ethyl ester

To a solution of 2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example100, 0.400 g, 1.756 mmol) and 1-formyl-cyclobutanecarboxylic acid ethylester (0.457 g, 2.633 mmol) in dichloromethane (13 mL) is added aceticacid (0.102 g, 1.756 mmol) and the mixture is refluxed. After 2 h, themixture is cooled with an ice-water bath and sodiumtri-acetoxyborohydride (1.175 g, 5.267 mmol) is added. After 13 h, themixture is heated to reflux for 1.5 h, cooled to room temperature,diluted with dichloromethane, washed with 1M aqueous NaOH, water andbrine. The combined aqueous phase is extracted once with dichloromethaneand the combined organic phase is dried over MgSO₄, filtered andconcentrated in vacuo. The residue is purified by silica gel flashchromatography (heptane-ethyl acetate, 1:1) to give1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylicacid ethyl ester as an oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.28 (t, J=7.1Hz, 3H), 1.99-2.12 (m, 4H), 2.49-2.59 (m, 2H), 3.53 (d, J=5.8 Hz, 2H),3.78 (s, 3H), 4.12-4.18 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 6.61 (d, J=0.8Hz, 1H), 7.04 (dd, J=2.8, 1.9 Hz, 1H), 7.15-7.19 (m, 1H), 7.26-7.30 (m,1H), 7.39 (dd, J=8.2, 0.8 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 8.09 (d,J=2.8 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H).

(c)1-{[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylicacid

To a solution of1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylicacid ethyl ester (0.107 g, 0.288 mmol) in THF (2 mL) and methanol (1 mL)is added aqueous lithium hydroxide (1M, 0.58 mL, 0.58 mmol) and thesolution is stirred overnight. The product is isolated by RP HPLC on anXbridge C18 eluting with an acetonitrile in 0.1% aqueous NH₄OH gradientto give1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylicacid as a white powder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.74-1.86 (m,1H), 1.87-1.97 (m, 3H), 2.26-2.35 (m, 2H), 3.33 (br. s., 1H), 3.39 (s,2H), 3.75 (s, 3H), 6.60 (s, 1H), 7.05-7.09 (m, 1H), 7.15 (m, 1H),7.17-7.21 (m, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.94(d, J=1.8 Hz, 1H), 8.06 (d, J=2.7 Hz, 1H). MS (ESI) m/z 336 (M+H)⁺.

Example 2142-Methyl-1-(1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutyl)-propan-1-one

To a solution of1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylicacid ethyl ester (Example 213b, 0.45 g, 1.21 mmol) in THF (150 mL)cooled with an ice-water bath is added iPrMgCl (2.0M in THF, 2.43 mL,4.85 mmol) dropwise. After 45 min, the mixture is quenched with 1Maqueous NaHSO₄ (5 mL), washed with saturated aqueous sodium bicarbonateand brine, dried over MgSO₄, filtered and concentrated in vacuo. Theresidue is purified by silica gel flash chromatography (heptane-ethylacetate, 3:2 to 1:1), followed by purification by RP HPLC on an XbridgeRP18 eluting with a gradient of acetonitrile in 0.1% aqueous NH₄OH togive2-methyl-1-(1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutyl)-propan-1-one.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (d, J=6.8 Hz, 6H), 1.68-1.78 (m,1H), 1.95-2.03 (m, 3H), 2.31-2.41 (m, 2H), 2.97-3.09 (m, 1H), 3.60 (d,J=5.7 Hz, 2H), 3.76 (s, 3H), 5.77 (t, J=5.7 Hz, 1H), 6.61 (s, 1H),7.06-7.10 (m, 1H), 7.16-7.25 (m, 2H), 7.51 (d, J=8.2 Hz, 1H), 7.58 (d,J=7.8 Hz, 1H), 7.99 (s, 1H), 8.12 (d, J=2.1 Hz, 1H). MS (ESI) m/z 362(M+H)⁺.

Example 2152-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-2-aza-spiro[3.3]heptan-1-one

The method described in Example 214 also affords2-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-2-aza-spiro[3.3]heptan-1-one.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.88-2.03 (m, 2H), 2.32-2.45 (m, 4H),3.77 (s, 3H), 3.83 (s, 2H), 6.71 (d, J=0.8 Hz, 1H), 7.06-7.14 (m, 1H),7.19-7.27 (m, 1H), 7.54 (m, 1H), 7.61 (m, 1H), 7.85 (dd, J=2.4, 1.9 Hz,1H), 8.54 (d, J=1.9 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H). MS (ESI) m/z 318.1(M+H)⁺.

Example 216 (a)1-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethanone

6-Chloro-1-methyl-indole-2-boronic acid and 5-acetyl-3-bromo-pyridineare processed according to the method described in Example 100 to give1-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethanone. MS (ESI)m/z 284.98 (M+H)⁺.

(b) 2-(5-Acetyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile

1-[5-(6-Chloro-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethanone isprocessed according to the method described in Example 128 to give2-(5-acetyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile. MS(ESI) m/z 310.07 (M+H)⁺.

(c)2-[5-(1-Amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile

Ammonium acetate (0.567 g, 7.207 mmol) is added to a solution of2-(5-acetyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(0.470 g, 1.441 mmol) in MeOH (10 mL), and the reaction is stirred at50° C. for 48 h. Sodium triacetoxyborohydride (2.251 g, 10.09 mmol) isadded and the reaction is stirred for 24 h at 50° C. Additional sodiumtriacetoxyborohydride (2.251 g, 10.09 mmol) is added and the reaction isstirred for another 24 h at 50° C. It is then diluted with ethyl acetateand washed with water thrice. The organic layer is dried over sodiumsulfate and concentrated in vacuo to give6-chloro-2-[5-(1-hydroxy-ethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrileand minor amounts of2-[5-(1-amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile.The mixture is redissolved in THF (5 mL) and phthalimide (0.181 g, 1.206mmol) and triphenylphosphine (0.172 g, 0.804 mmol) are added, followedwith di-isopropylazodicarboxylate (0.157 mL, 0.804 mmol). The reactionis stirred at room temperature for 4 h. It is then diluted with ethylacetate and washed with water thrice. The organic layer is dried oversodium sulfate and concentrated in vacuo, to give a residue which ispurified by silica gel flash chromatography (heptane-ethyl acetate, 1:1)to afford a mixture of6-chloro-2-{5-[1-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-pyridin-3-yl}-1-methyl-1H-indole-3-carbonitrileand triphehyl phosphine. The mixture is redissolved in ethanol (5 mL).Hydrazine hydrate (65%) (0.411 mL, 8.506 mmol) is added and the reactionis stirred at room temperature overnight. It is then acidified with 2Maqueous HCl and concentrated in vacuo. The residue is redissolved indichloromethane and filtered through celite to remove the precipitateformed. The organic layer is washed with water. The aqueous layer isseparated and basified to with 4M aqueous NaOH, and then extracted withdichloromethane thrice. The organic layer is dried over sodium sulfateand concentrated in vacuo to afford2-[5-(1-amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrileas a solid. MS (ESI) m/z 311.1 (M+H)⁺

(d) Ethanesulfonic acid{1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethyl}-amide

A flask is charged with2-[5-(1-amino-ethyl)-pyridin-3-yl]-6-chloro-1-methyl-1H-indole-3-carbonitrile(0.072 g, 0.209 mmol) and dichloromethane (3 mL). Ethanesulfonylchloride (0.060 g, 0.525 mmol) and triethylamine (0.059 mL, 0.417 mmol)are added and the reaction is stirred at room temperature overnight. Thereaction mixture is concentrated in vacuo to give a residue which ispurified by silica gel flash chromatography (heptane-ethyl acetate, 1:1)to afford ethanesulfonic acid{1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethyl}-amideas a white solid. ¹H NMR (400 MHz, MeOD) δ ppm 1.32 (t, J=7.5 Hz, 3H),1.65 (d, J=7.1 Hz, 3H), 2.96-3.15 (m, 2H), 3.84 (s, 3H), 4.75-4.86 (m,1H), 7.39 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.78 (d,J=1.5 Hz, 1H), 8.20 (t, J=2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 8.83 (d,J=2.3 Hz, 1H). HRMS (ESI) m/z 403.1005 [(M+H)⁺Calcd for C₁₉H₂₀N₄O₂SCl:403.0996].

(e) (R) and (S)-ethanesulfonic acid{1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethyl}-amide

Racemic ethanesulfonic acid{1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethyl}-amideis resolved by chiral chromatography using a Chiralpak® AS column,eluting with a 3:2 heptane-ethanol mixture to give (R) and(S)-ethanesulfonic acid{1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-ethyl}-amide.The retention times are 6.9 and 9.2 min at 0.8 mL/min on an analyticalChiralpak® AS column.

Example 217 (a) 3-Bromo-5-(2-methoxy-vinyl)-pyridine

A flask is charged with methoxymethyltriphenylphosphine chloride (3.04g, 8.87 mmol) and tetrahydrofuran (20 mL). The mixture is cooled to −78°C. and sodium hexamethyldisilazane (1M solution in THF, 9.60 mL, 9.67mmol) is added dropwise. The reaction mixture is stirred at −78° C. for30 min, whereupon 5-bromo-pyridine-3-carbaldehyde (1.5 g, 8.06 mmol) isadded. The mixture is allowed to warm to room temperature and stirredovernight. Purification by silica gel flash chromatography(heptane-ethyl acetate, 4:1) affords an E/Z mixture of3-bromo-5-(2-methoxy-vinyl)-pyridine as a colorless oil. MS (ESI) m/z215.95 (M+H)⁺.

(b) 2-[5-(2-Methoxy-vinyl)-pyridin-3-yl]-1-methyl-1H-indole

3-Bromo-5-(2-methoxy-vinyl)-pyridine is processed according to themethod described in Example 106b to give an E/Z mixture of2-[5-(2-methoxy-vinyl)-pyridin-3-yl]-1-methyl-1H-indole as an oil. MS(ESI) m/z 265.20 (M+H)⁺.

(c) 2-[5-(2-Methoxy-ethyl)-pyridin-3-yl]-1-methyl-1H-indole

A flask is charged with2-[5-(2-methoxy-vinyl)-pyridin-3-yl]-1-methyl-1H-indole (0.550 g, 2.08mmol) and methanol (5 mL). Palladium on carbon (0.221 g, 0.208 mmol) isadded and the reaction mixture is stirred at 50° C. under H₂ for 16 h.It is then cooled to room temperature and filtered through celite. Thecelite layer is thoroughly washed with methanol. The filtrate isconcentrated in vacuo, to give a residue which is purified by silica gelflash chromatography (heptane-ethyl acetate, 7:3) to afford2-[5-(2-methoxy-ethyl)-pyridin-3-yl]-1-methyl-1H-indole as an oil. MS(ESI) m/z 267.36 (M+H)⁺.

(d)2-[5-(2-Methoxy-ethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile

2-[5-(2-Methoxy-ethyl)-pyridin-3-yl]-1-methyl-1H-indole is processedaccording to the method described in Example 128 to give2-[5-(2-methoxy-ethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrileas a solid. ¹H NMR (400 MHz, MeOD) δ ppm 3.09 (t, J=6.2 Hz, 2H), 3.41(s, 3H), 3.76 (t, J=6.3 Hz, 2H), 3.87 (s, 3H), 7.36-7.42 (m, 1H),7.44-7.51 (m, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.75 (dd, J=7.8, 1.1 Hz, 1H),8.10 (t, J=2.1 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H).HRMS (ESI) m/z 292.1458 [(M+H)⁺Calcd for C₁₈H₁₈N₃O: 292.1450].

Example 218 1-Difluoromethyl-2-pyridin-3-yl-1H-indole-3-carbonitrile

A flask is charged with 2-pyridin-3-yl-1H-indole-3-carbonitrile (Example83b, 340 mg, 1.55 mmol) and DMF (10 mL), and 60% NaH in mineral oil (68mg, 1.71 mmol) is added. The mixture is stirred at room temperature for20 min. CClF₂H is bubbled into the reaction mixture while the reactiontemperature is raised to 100° C. The reaction temperature is raised to150° C. for 30 min. The mixture is cooled to room temperature and water(1 mL) is added. The mixture is then filtered and the filtrate ispurified on Xbridge C18 eluting with a 1:9 to 9:1 acetonitrile-watergradient to give1-difluoromethyl-2-pyridin-3-yl-1H-indole-3-carbonitrile. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.48-7.53 (m, 1H), 7.56 (td, J=7.7, 1.3 Hz, 1H),7.68-7.73 (m, 1H), 7.86 (t, J=56.6 Hz, 1H), 7.86 (dd, J=37.6, 8.1 Hz,1H), 7.91 (d, J=8.3 Hz, 1H), 8.13 (dt, J=8.0, 2.0, 1.9 Hz, 1H), 8.85(dd, J=4.9, 1.6 Hz, 1H), 8.87 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 270.0841[(M+H)⁺ Calcd for C₁₅H₁₀F₂N₃: 270.0843].

Example 219 Ethanesulfonic acid[5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide

2-(5-Formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example127) and ethanesulfonamide are processed according to the methoddescribed in Example 170 to give ethanesulfonic acid[5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.20 (t, J=7.3 Hz, 3H), 3.07 (q, J=7.4 Hz, 2H),3.79 (s, 3H), 4.34 (d, J=6.1 Hz, 2H), 7.34-7.38 (m, 1H), 7.41-7.46 (m,1H), 7.72 (d, J=7.6 Hz, 1H), 7.75-7.82 (m, 2H), 8.09 (t, J=2.1 Hz, 1H),8.77 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.1 Hz, 1H). HRMS (ESI) m/z 355.1247[(M+H)⁺Calcd for C₁₈H₁₉N₄O₂S: 355.1229].

Example 2202-(5-Hydroxymethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

The method described in Example 219 using2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example127) also affords2-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile as aproduct of the reaction. MS (ESI) m/z 264.07 (M+H)⁺.

Example 221 (a)2-[5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile

To a solution of2-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile(Example 220, 190 mg, 0.72 mmol) in THF (5 mL) are added sequentiallyphthalimide (116 mg, 0.79 mmol), 1,1′-(azodicarbonyl)dipiperidine (346mg, 1.37 mmol) and tributylphosphine (277 mg, 1.37 mmol). The mixture isstirred at room temperature overnight. The mixture is then concentratedin vacuo and the residue is purified by silica gel flash chromatography(heptane-ethyl acetate, 1:0 to 0:1) to give2-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile.MS (ESI) m/z 393.02 (M+H)⁺.

(b) 2-(5-Aminomethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile

To a solution of2-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile(200 mg, 0.51 mmol) in ethanol (15 mL) is added hydrazine hydrate (327mg, 10.2 mmol). The mixture is stirred at room temperature overnight.The reaction mixture is poured into dichloromethane (100 mL) andextracted with 1M HCl in water. The combined aqueous phase is basifiedwith 5M NaOH in water and extracted with dichloromethane. The combinedorganic phase is dried over Na₂SO₄ and concentrated in vacuo to give2-(5-aminomethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile, whichis used in the next step without further purification. MS (ESI) m/z263.27 (M+H)⁺.

(c) Propane-2-sulfonic acid[5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide

A flask is charged with2-(5-aminomethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (130mg, 0.5 mmol), DBU (304 mg, 2.0 mmol) and DCE (15 mL), andisopropylsulfonyl chloride (142 mg, 1.0 mmol) is added. The mixture isstirred at room temperature for 1 h and concentrated in vacuo. Theresidue is purified by silica gel flash chromatography(dichloromethane-methanol, 1:0 to 97:3) to give propane-2-sulfonic acid[5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.24 (d, J=6.8 Hz, 6H), 3.18-3.26 (m, 1H), 3.79(s, 3H), 4.37 (d, J=6.1 Hz, 2H), 7.34-7.38 (m, 1H), 7.41-7.46 (m, 1H),7.70-7.79 (m, 3H), 8.08 (t, J=2.0 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.81(d, J=2.3 Hz, 1H). HRMS (ESI) m/z 369.1389 [(M+H)⁺Calcd for C₁₉H₂₁N₄O₂S:369.1385].

Example 222 Trifluoromethanesulfonic acid[5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide

2-(5-Formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example127) and trifluoromethanesulfonamide are processed according to themethod described in Example 170 to give trifluoromethanesulfonic acid[5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 3.79 (s, 3H), 4.58 (s, 2H), 7.34-7.39 (m, 1H),7.42-7.47 (m, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 8.10(t, J=2.1 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H), 8.85 (d, J=2.1 Hz, 1H), 10.19(br. s, 1H). HRMS (ESI) m/z 395.0779 [(M+H)⁺Calcd for C₁₇H₁₄F₃N₄O₂S:395.0790].

Example 223 Propane-2-sulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide

2-(5-Amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 211) is processed according to the method described in Example221c to give to give propane-2-sulfonic acid[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.30 (d, J=6.8 Hz, 6H), 3.46 (dq, J=6.8 Hz,1H), 3.79 (s, 3H), 7.37 (dd, J=8.5, 1.9 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H),7.93 (t, J=2.1 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H),8.63 (d, J=2.5 Hz, 1H), 10.41 (s, 1H). HRMS (ESI) m/z 389.0836 [(M+H)⁺Calcd for C₁₈H₁₈ClN₄O₂S: 389.0839].

Example 224N′-[5-(6-Chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N,N-dimethyl-formamidine

To a solution of2-(5-amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile(Example 211, 85 mg, 0.3 mmol) in DMF (5 mL) is added 60% NaH in mineraloil (48 mg, 1.2 mmol), followed with propane-2-sulfonyl chloride (86 mg,60.6 mmol). The mixture is stirred at room temperature for 5 h. Themixture is filtered and the filtrate is purified on Xbridge C18 elutingwith a 1:9 to 9:1 acetonitrile-water gradient to giveN′-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N,N-dimethyl-formamidine.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.98 (s, 3H), 3.06 (s, 3H), 3.79 (s,3H), 7.35 (dd, J=8.3, 1.8 Hz, 1H), 7.62 (t, J=2.1 Hz, 1H), 7.70 (d,J=8.3 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 7.96 (s, 1H), 8.37-8.39 (m, 2H).HRMS (ESI) m/z 338.1182 [(M+H)⁺ Calcd for C₁₈H₁₇ClN₅: 338.1173].

Example 225 (a) Ethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide

To a solution of 2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example100) (223 mg, 1.0 mmol) in dichloromethane (20 mL) is addedethanesulfonyl chloride (386 mg, 3.0 mmol) and di-isopropylethylamine(517 mg, 4.0 mmol). The mixture is stirred at room temperature for 1 h.Saturated NaHCO₃ in water (0.5 mL) and silica gel (10 g) are added andthe mixture is concentrated in vacuo. The residue is purified by silicagel chromatography (heptane-ethyl acetate, 1:0 to 1:9) to giveethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide. MS(ESI) m/z 408.1 (M+H)⁺.

(b) Ethanesulfonic acid[5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide

Ethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide isprocessed according to the method described in Example 128 to giveethanesulfonic acid[5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide.MS (ESI) m/z 432.96 (M+H)⁺.

(c) Ethanesulfonic acid[5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide

A solution of ethanesulfonic acid[5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amidein DMF (2 mL), methanol (10 mL) and 5 M NaOH in water (1 mL) is stirredat room temperature for 1 h. The mixture is purified on Xbridge C18eluting with a 1:9 to 9:1 acetonitrile-water gradient to giveethanesulfonic acid[5-(3-cyano-1-methyl-1-indol-2-yl)-pyridin-3-yl]-amide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.25 (t, J=7.3 Hz, 3H), 3.24-3.32 (m, 2H), 3.80 (s, 3H),7.32-7.38 (m, 1H), 7.43 (td, J=7.8, 1.1 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H),7.75 (d, J=8.3 Hz, 1H), 7.90 (t, J=2.3 Hz, 1H), 8.58-8.62 (m, 2H), 10.42(s, 1H). HRMS (ESI) m/z 341.1078 [(M+H)⁺Calcd for C₁₇H₁₇N₄O₂S:341.1072].

Example 226 Ethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide

Ethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide(Example 225a) is processed according to the method described in Example225c to give ethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.26 (t, J=7.3 Hz, 3H), 3.26 (q, J=7.3 Hz, 2H), 3.77 (s,3H), 6.71 (s, 1H), 7.08-7.13 (m, 1H), 7.20-7.27 (m, 1H), 7.54 (d, J=8.1Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.79 (t, J=2.3 Hz, 1H), 8.48 (d, J=2.5Hz, 1H), 8.56 (d, J=1.8 Hz, 1H), 10.23 (s, 1H). HRMS (ESI) m/z 316.1125[(M+H)⁺Calcd for C₁₆H₁₈N₃O₂S: 316.1120].

Example 227 Methanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide

2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example 100) andmethanesulfonyl chloride are processed according to the methodsdescribed in Example 225a and 225c to give methanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.15 (s, 3H), 3.77 (s, 3H), 6.71 (s, 1H), 7.06-7.13 (m,1H), 7.23 (ddd, J=8.2, 7.1, 1.1 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.61(d, J=7.6 Hz, 1H), 7.79 (t, J=2.2 Hz, 1H), 8.48 (d, J=2.3 Hz, 1H), 8.58(d, J=2.0 Hz, 1H), 10.18 (s, 1H). HRMS: (ESI) m/z 302.0966 [(M+H)⁺Calcdfor C₁₆H₁₆N₃O₂S 302.0958].

Example 228 Diethyl-sulfamic acid5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl-amide

To a solution of 2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example100, 60 mg, 0.269 mmol) and dimethylsulfamoyl chloride (58 mg, 0.403mmol) in dichloromethane (1 mL) is added triethylamine (54 mg, 0.537mmol). After overnight stirring, the mixture is concentrated andpurified by silica gel flash chromatography (heptane-ethyl acetate, 3:7)to give diethyl-sulfamic acid5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl-amide. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 2.77 (s, 6H), 3.76 (s, 3H), 6.89 (s, 1H), 7.07-7.12 (m, 1H),7.20-7.25 (m, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.75(t, J=2.1 Hz, 1H), 8.46 (d, J=2.5 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H). HRMS:(ESI) m/z 331.1226 [(M+H)⁺ Calcd for C₁₆H₁₈N₄O₂S 331.1223].

Example 229 (a) Ethanesulfonic acid[5-(1-methyl-3-carboxaldehyde-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide

A flask is charged with DMF (10 mL) and cooled to 0° C. Phosphorusoxychloride (0.297 ml, 3.19 mmol) is added and the reaction mixture isstirred at 0° C. for 20 min followed by the addition of a solution ofethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide(Example 225a, 1.00 g, 2.454 mmol) in DMF (10 mL). The reaction mixtureis stirred at room temperature for 16 h. The reaction is stopped, washedwith saturated NaHCO₃ solution and extracted with ethyl acetate. Theorganic layer is separated and washed with water thrice, then dried overNa₂SO₄ and concentrated in vacuo to afford ethanesulfonic acid[5-(1-methyl-3-carboxaldehyde-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide.MS (ESI) m/z 436.2 (M+H)⁺

(b) Ethanesulfonic acid[5-(1-methyl-3-vinyl-1H-indol-2-yl)-pyridin-3-yl]-amide

A flask is charged with methyl triphenyl phosphine bromide (0.492 g,1.378 mmol) and THF (20 mL). The reaction mixture is cooled to −78° C.and 1M NaHMDS in THF (1.515 ml, 1.515 mmol) is added. The reaction isstirred at −78° C. for 1 h followed by the addition of ethanesulfonicacid[5-(1-methyl-3-carboxaldehyde-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide(0.300 g, 0.689 mmol) at −78° C. The reaction mixture is allowed to warmto room temperature and stirred overnight. The mixture is washed withwater and extracted with ethyl acetate. The organic layer is dried oversodium sulfate and concentrated in vacuo. The crude is purified bysilica gel flash chromatography (heptane-ethyl acetate, 1:0 to 0-1) toafford ethanesulfonic acid[5-(1-methyl-3-vinyl-1H-indol-2-yl)-pyridin-3-yl]-amide product. MS(ESI) m/z 342.2 (M+1-1)⁺

(c) Ethanesulfonic acid[5-(1-methyl-3-ethyl-1H-indol-2-yl)-pyridin-3-yl]-amide

A flask is charged with ethanesulfonic acid[5-(1-methyl-3-vinyl-1H-indol-2-yl)-pyridin-3-yl]-amide (35 mg, 0.082mmol) and MeOH (5 mL). The flask is evacuated and flushed with N₂thrice. Pd/C (4.36 mg) is added and the reaction stirred under H₂overnight at 50° C. The reaction is filtered over celite and the celitelayer is washed thoroughly with MeOH. The filtrate is concentrated invacuo. The crude is purified by silica gel flash chromatography(dichloromethane-methanol, 19:1) followed by HPLC purification usingXbridge C18 eluting with a 10 to 100% acetonitile-water gradient toafford the pure product ethanesulfonic acid[5-(3-ethyl-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. ¹H NMR (400MHz, MeOD) δ ppm 1.27 (t, J=7.6 Hz, 3H), 1.40 (t, J=7.3 Hz, 3H), 2.76(q, J=7.6 Hz, 2H), 3.25 (q, J=7.3 Hz, 2H), 3.66 (s, 3H), 7.09-7.17 (m,1H), 7.23-7.31 (m, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H),7.83 (t, J=2.3 Hz, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H).HRMS: (ESI) m/z 344.1435 [(M+H)⁺Calcd for C₁₈H₂₁N₃O₂3 344.1427].

Example 230 Ethanesulfonic acid(2-hydroxy-ethyl)-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide

A flask is charged with ethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide (Example 226, 200 mg,0.634 mmol) and DMF (3 mL). The reaction is cooled to 0° C. and sodiumhydride (38.0 mg, 0.951 mmol) is added. The reaction is stirred at roomtemperature for 10 min, then 2-chloro-ethoxytrimethylsilane (0.154 mL,0.951 mmol) is added. The reaction is stirred at 100° C. for 16 h thencooled to room temperature. Aqueous 1M HCl (1 mL) is added and stirringis continued for 30 min. The mixture is purified using an Xbridge C18eluting with a 10 to 100% acetonitrile-water gradient to affordethanesulfonic acid(2-hydroxy-ethyl)-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. MS(ESI) m/z 360.1 (M+1-1)⁺. ¹H NMR (400 MHz, MeOD) δ ppm 1.42 (t, J=7.3Hz, 3H), 3.29 (t, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.84 (s, 3H), 3.96 (t,J=5.6 Hz, 2H), 6.75 (s, 1H), 7.14 (td, J=7.5, 0.9 Hz, 1H), 7.28 (td,J=7.7, 1.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 8.18(t, J=2.1 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.75 (d, J=1.8 Hz, 1H). HRMS(ESI) m/z 360.1383 [(M+1-1)⁺Calcd for C₁₈H₁₂N₃O₃S 360.1376].

Example 231 Ethanesulfonic acidmethyl-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide

A flask is charged with ethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide (Example 226, 100 mg,0.317 mmol) and DMF (4 mL). The reaction is cooled to 0° C. and sodiumhydride (15.85 mg, 0.396 mmol) is added. The reaction is stirred at 0°C. for 10 min, then methyl iodide (56.3 mg, 0.396 mmol) is added. Thereaction is stirred for 1 hour at room temperature. The reaction isquenched with water (0.5 mL) and filtered. The filtrate is purifiedusing Xbridge C18 eluting with a 10 to 100% acetonitrile-water gradientto afford ethanesulfonic acidmethyl-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. ¹H NMR (400 MHz,MeOD) δ ppm 1.39 (t, J=7.5 Hz, 3H), 3.28 (q, J=7.5 Hz, 2H), 3.49 (s,3H), 3.84 (s, 3H), 6.74 (s, 1H), 7.14 (t, J=7.6 Hz, 1H), 7.28 (ddd,J=7.6, 1.1 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.13(t, J=2.1 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H), 8.70 (d, J=2.5 Hz, 1H). HRMS(ESI) m/z 330.1281 [(M+H)⁺ Calcd for C₁₇H₁₉N₃O₂S 330.1270].

Example 232 (a) 2-(5-Bromo-pyridin-3-yl)-isoindole-1,3-dione

A flask is charged with 3-amino-5-bromo pyridine (1.00 g, 5.78 mmol),phthalic anhydride (0.856 g, 5.78 mmol) and acetic acid (20 mL). Thereaction is refluxed overnight. The reaction is then cooled to roomtemperature and concentrated in vacuo. The crude is dissolved in ethylacetate and washed with water once. The organic layer is dried oversodium sulfate and concentrated in vacuo to afford2-(5-bromo-pyridin-3-yl)-isoindole-1,3-dione. MS (ESI) m/z 305.1 (M+H)⁺

(b) 2-[5-(6-Methyl-1H-indol-2-yl)-pyridin-3-yl]-isoindole-1,3-dione

2-(5-Bromo-pyridin-3-yl)-isoindole-1,3-dione andN-Boc-6-methyl-indoleboronic acid are processed according to theprocedure described in Example 103 to give2-[5-(6-methyl-1H-indol-2-yl)-pyridin-3-yl]-isoindole-1,3-dione. MS(ESI) m/z 354.1 (M+H)⁺

(c) 2-[5-(1,6-DiMethyl-1H-indol-2-yl)-pyridin-3-yl]-isoindole-1,3-dione

2-[5-(6-methyl-1H-indol-2-yl)-pyridin-3-yl]-isoindole-1,3-dione isprocessed according to the procedure described in Example 114 to give2-[5-(1,6-dimethyl-1H-indol-2-yl)-pyridin-3-yl]-isoindole-1,3-dione. MS(ESI) m/z 368.3 (M+H)⁺

(d) 5-(1,6-Dimethyl-1H-indol-2-yl)-pyridin-3-ylamine

A flask is charged with2-[5-(1,6-dimethyl-1H-indol-2-yl)-pyridin-3-yl]-isoindole-1,3-dione(1.10 g, 2.096 mmol) and EtOH (30 mL). Hydrazine (1.316 mL, 41.9 mmol)is added and the reaction mixture is refluxed for 1 hour. The reactionmixture is cooled to room temperature, filtered and the precipitate iswashed thoroughly with ethyl acetate. The filtrate is concentrated invacuo. The crude is taken up 1M HCl solution and then extracted withEtOAc. The aqueous layer is separated, basified to pH 14 using 4Maqueous NaOH and extracted with DCM thrice. The organic layer is driedover Na₂SO₄ and concentrated in vacuo to afford5-(1,6-dimethyl-1H-indol-2-yl)-pyridin-3-ylamine. MS (ESI) m/z 238.4(M+H)⁺

(e) Ethanesulfonic acid[5-(1,6-dimethyl-1H-indol-2-yl)-pyridin-3-yl]-amide

5-(1,6-Dimethyl-1H-indol-2-yl)-pyridin-3-ylamine is processed accordingto the procedures described in Example 225a and 225c to giveethanesulfonic acid [5-(1,6-dimethyl-1H-indol-2-yl)-pyridin-3-yl]-amide.¹H NMR (400 MHz, MeOD) δ ppm 1.40 (t, J=7.3 Hz, 3H), 2.53 (s, 3H), 3.26(q, J=7.3 Hz, 2H), 3.79 (s, 3H), 6.65 (s, 1H), 6.98 (d, J=8.1 Hz, 1H),7.28 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.93 (t, J=2.3 Hz, 1H), 8.46 (d,J=2.3 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 330.1285[(M+1-1)⁺Calcd for C₁₇H₁₉N₃O₂S 330.1270].

Example 233 Ethanesulfonic acid[5-(1,6-dimethyl-3-cyano-1H-indol-2-yl)-pyridin-3-yl]-amide

5-(1,6-Dimethyl-1H-indol-2-yl)-pyridin-3-ylamine (Example 232d) isprocessed according to the procedures described in Example 225a, 128 and225c to give ethanesulfonic acid[5-(1,6-dimethyl-3-cyano-1H-indol-2-yl)-pyridin-3-yl]-amide. ¹H NMR (400MHz, MeOD) d ppm 1.39 (t, J=7.3 Hz, 3H), 2.57 (s, 3H), 3.22 (q, J=7.3Hz, 2H), 3.84 (s, 3H), 7.22 (d, J=8.1 Hz, 1H), 7.46 (s, 1H), 7.60 (d,J=8.1 Hz, 1H), 7.92-7.94 (m, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.50 (d, J=2.5Hz, 1H). HRMS: (ESI) m/z 355.1230 [(M+H)⁺Calcd for C₁₈H₁₈N₄O₂S355.1223].

Example 234 Ethanesulfonic acid[5-(1-methyl-6-fluoro-1H-indol-2-yl)-pyridin-3-yl]-amide

6-Fluoro-1-methyl-indole boronic acid and 3-bromo-5-aminopyridine areprocessed according to procedures described in examples 100, 225a and225c to give ethanesulfonic acid[5-(1-methyl-6-fluoro-1H-indol-2-yl)-pyridin-3-yl]-amide. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.24 (t, J=7.3 Hz, 3H), 3.17-3.28 (m, 5H), 6.53 (d,J=3.0 Hz, 1H), 7.01 (dd, J=10.2, 8.7 Hz, 1H), 7.29 (d, J=3.3 Hz, 1H),7.60-7.68 (m, 2H), 8.41 (d, J=1.8 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 10.23(s, 1H). HRMS (ESI) m/z 334.1029 [(M+H)⁺Calcd for C₁₆H₁₆FN₃O₂S334.1020].

Example 235 (a) Bis-ethanesulfonic acid[5-(1-methyl-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide

Bis-ethanesulfonic acid (5-bromo-pyridin-3-yl)-amide (Example 210a) and6-chloro-1-methyl-indole-2-boronic acid are processed according to theprocedure described in Example 100 to give bis-ethanesulfonic acid[5-(1-methyl-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide. MS (ESI) m/z442.1 (M+H)⁺

(b) Bis-ethanesulfonic acid[5-(1-methyl-3-carboxaldehyde-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide

A flask is charged with DMF (10 mL) and cooled to 0° C. Phosphorusoxychloride (0.205 ml, 2.178 mmol) is added and the reaction mixture isstirred for 20 min. Bis-ethanesulfonic acid[5-(1-methyl-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide (0.875 g, 1.980mmol) is added and reaction mixture is left to stir at room temperatureovernight. The reaction is washed with saturated aqueous NaHCO₃ andextracted with ethyl acetate. The organic layer is separated and washedwith water thrice, then dried over Na₂SO₄ and concentrated in vacuo toafford bis-ethanesulfonic acid[5-(1-methyl-3-carboxaldehyde-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide.MS (ESI) m/z 469.9 (M+H)⁺.

(c) Bis-ethanesulfonic acid[5-(1,3-dimethyl-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide

A flask is charged with bis-ethanesulfonic acid[5-(1-methyl-3-carboxaldehyde-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide(0.225 g, 0.479 mmol), zinc iodide (0.2320 g, 0.718 mmol), NaCN(BH)₃(0.228 g, 3.591 mmol) and dichloroethane (5 mL). The reaction isrefluxed for 1.5 hours. The reaction mixture is cooled to roomtemperature and filtered over celite. The celite layer is washed withDCM. The filtrate is washed with a buffer solution containing 1:1saturated ammonium hydroxide and saturated ammonium chloride solution.The organic layer is dried over sodium sulfate and concentrated in vacuoto give bis-ethanesulfonic acid[5-(1,3-dimethyl-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide. MS (ESI)m/z 455.9 (M+H)⁺

(d) Ethanesulfonic acid[5-(1,3-dimethyl-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide

Bis-ethanesulfonic acid[5-(1,3-dimethyl-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide isprocessed according to the procedure described in Example 225c to giveethanesulfonic acid[5-(1,3-dimethyl-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide. ¹H NMR(400 MHz, MeOD) δ ppm 1.41 (t, J=7.33 Hz, 3H), 2.31 (s, 3H), 3.26 (q,J=7.33 Hz, 2H), 3.67 (s, 3H), 7.12 (dd, J=8.46, 1.89 Hz, 1H), 7.49 (d,J=1.77 Hz, 1H), 7.57 (d, J=8.34 Hz, 1H), 7.81-7.86 (m, 1H), 8.41 (d,J=1.77 Hz, 1H), 8.51 (d, J=2.27 Hz, 1H). HRMS (ESI) m/z 364.0894[(M+H)⁺Calcd for C₁₇H₁₈N₃O₂SCl 364.0881].

Example 236 Ethanesulfonic acid[5-(1,3-dimethyl-1H-indol-2-yl)-pyridin-3-yl)-amide

Ethanesulfonic acid[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-N-ethanesulfonyl-amide(Example 225a) is processed according to the procedures described inExample 235b, 235c and 225c to give ethanesulfonic acid[5-(1,3-dimethyl-1H-indol-2-yl)-pyridin-3-yl)-amide. ¹H NMR (400 MHz,MeOD) δ ppm 1.41 (t, J=7.5 Hz, 3H), 2.33 (s, 3H), 3.27 (q, J=7.3 Hz,2H), 3.69 (s, 3H), 7.14 (t, J=7.5 Hz, 1H), 7.24-7.31 (m, 1H), 7.43 (d,J=8.3 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.84 (t, J=2.1 Hz, 1H), 8.42 (d,J=1.8 Hz, 1H), 8.50 (d, J=2.5 Hz, 1H). HRMS: (ESI) m/z 330.1276[(M+H)⁺Calcd for C₁₇H₁₉N₃O₂S 330.1270].

Example 237 (a) N-((5-bromopyridin-3-yl)methyl)ethanesulfonamide

A flask is charged with 5-bromonicotinaldehyde (1.15 g, 6.18 mmol),ethanesulfonamide (1.35 g, 12.37 mmol) and toluene (120 mL), andtitanium isopropoxide (2.64 g, 9.27 mmol) is added dropwise. The mixtureis stirred at 120° C. overnight. The mixture is concentrated in vacuo.The residue is taken up in DCM (100 mL) and MeOH (100 mL) and NaBH₄(0.468 g, 12.37 mmol) is added at 0° C. The mixture is stirred at 0° C.for 30 min. Water (50 mL) is then added and the mixture is stirred for 5min. The suspension is filtered through a pad of celite. The celitelayer is washed with DCM (50 mL×3). The filtrate is concentrated invacuo. The resulting aqueous phase is extracted with DCM (500 mL) andthe organic phase is dried over Na₂SO₄, silica gel (20 g) added, andconcentrated in vacuo. The residue is purified by silica chromatographyeluting with a 0 to 7% MeOH-DCM gradient to giveN-((5-bromopyridin-3-yl)methyl)ethanesulfonamide. MS (ESI) m/z 278.9,280.8, (M+H)⁺.

(b) N-((5-Bromopyridin-3-yl)methyl)-1-(ethylsulfonyl)ethanesulfonamide

To a solution of N-((5-bromopyridin-3-yl)methyl)ethanesulfonamide (1.8g, 5.55 mmol) and triethylamine (1.683 g, 16.64 mmol) in DCM (20 mL) at0° C. is added ethanesulfonyl chloride (1.426 g, 11.09 mmol), and themixture is stirred at 0° C. for 1 h. Silica gel (10 g) is added and themixture is concentrated in vacuo. The residue is purified by silicachromatography eluting with 0 to 2% MeOH-DCM to giveN-((5-bromopyridin-3-yl)methyl)-N-(ethylsulfonyl)ethanesulfonamide. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.14 (t, J=7.3 Hz, 6H), 3.48 (q, J=7.3 Hz,4H), 4.92 (s, 2H), 8.0 (t, J=2.1 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.72(d, J=2.3 Hz, 1H).

(c)N-(Ethylsulfonyl)-N-((5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)methyl)ethanesulfonamide

N-((5-Bromopyridin-3-yl)methyl)-1-(ethylsulfonyl)ethanesulfonamide andN-methyl-indole-2-boronic acid are processed according to the proceduredescribed in Example 100 to giveN-(ethylsulfonyl)-N-((5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)methyl)ethanesulfonamide.MS (ESI) m/z 422.0 (M+H)⁺.

(d)N-(Ethylsulfonyl)-N-((5-(3-formyl-1-methyl-1H-indol-2-yl)pyridin-3-yl)methyl)ethanesulfonamide

N-(Ethylsulfonyl)-N-((5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)methyl)ethanesulfonamideis processed according to the procedure described in Example 235b togiveN-(ethylsulfonyl)-N-((5-(3-formyl-1-methyl-1H-indol-2-yl)pyridin-3-yl)methyl)ethanesulfonamide.MS (ESI) m/z 450.0 (M+H)⁺.

(e)N-((5-(1,3-Dimethyl-1H-indol-2-yl)pyridin-3-yl)methyl)ethanesulfonamide

N-(Ethylsulfonyl)-N-((5-(3-formyl-1-methyl-1H-indol-2-yl)pyridin-3-yl)methyl)ethanesulfonamideis processed according to the procedure described in Example 235c togiveN-(ethylsulfonyl)-N-((5-(1,3-dimethyl-1H-indol-2-yl)pyridin-3-yl)methyl)ethanesulfonamidewhich is processed according to the procedure described in Example 225cto giveN-((5-(1,3-dimethyl-1H-indol-2-yl)pyridin-3-yl)methyl)ethanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (t, J=7.3 Hz, 3H), 2.24 (s, 3H),3.04 (q, J=7.3 Hz, 2H), 3.62 (s, 3H), 4.31 (s, 2H), 7.10 (t, J=7.5 Hz,1H), 7.22 (ddd, J=8.2, 7.0, 1.3 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.58(d, J=7.8 Hz, 1H), 7.72 (br. s., 1H), 7.87 (t, J=2.0 Hz, 1H), 8.61 (dd,J=7.2, 2.2 Hz, 2H). HRMS: (ESI) m/z 344.1442 [(M+H)+ Calcd forC₁₈H₂₂N₃O₂S: 344.1427].

Example 238 (a) Ethanesulfonic acid[5-(1-methyl-3-methoxymethyl-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide

Bis-ethanesulfonic acid[5-(1-methyl-3-carboxaldehyde-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide(Example 235b, 0.150 g, 0.319 mmol) is dissolved in methanol (5 mL) andcooled to 0° C. NaBH₄ (0.019 g, 0.798 mmol) is added and the reactionmixture is stirred at room temperature for 2 h. 4M aqueous NaOH (1 mL)is added and the reaction is stirred at room temperature for 1 h. Themethanol is then removed in vacuo. The crude is taken up in DCM andwashed with water twice. The organic layer is dried over Na₂SO₄ andconcentrated in vacuo. The crude is purified by silica gel flashchromatography (dichloromethane-methanol, 9:1) to affordbis-ethanesulfonic acid[5-(1-methyl-3-methoxymethyl-6-chloro-1H-indol-2-yl)-pyridin-3-yl)-amide.¹H NMR (400 MHz, MeOD) δ ppm 1.41 (t, J=7.3 Hz, 3H), 3.28 (q, J=7.3 Hz,2H), 3.39 (s, 3H), 3.72 (s, 3H), 4.54 (s, 2H), 7.18 (dd, J=8.6, 1.8 Hz,1H), 7.56 (d, J=1.8 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.93 (t, J=2.3 Hz,1H), 8.48 (d, J=1.8 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H). HRMS: (ESI) m/z394.0990 [(M+H)⁺ Calcd for C₁₈H₂₀N₃O₃SCl 394.0986].

Example 239 (a)2-(Benzyloxy)-N-(5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)ethanesulfonamide

To a solution of 5-(1-methyl-1H-indol-2-yl)pyridin-3-amine (Example 100,150 mg, 0.672 mmol) and triethylamine (272 mg, 2.69 mmol) in DCM (6 mL)is added 2-chloroethanesulfonyl chloride (274 mg, 1.68 mmol) in DCM (2mL) dropwise at 0° C. The mixture is stirred at 0° C. for 1 h. Silicagel (5 g) is added and the mixture is concentrated. After elution, thefractions containing the product are concentrated to give a residue,which is redissolved in benzyl alcohol (20 mL). 60% NaH in mineral oilis added. The mixture is stirred at 70° C. for 1 day. The mixture isthen filtered and the filtrate is purified on Xbridge C18 eluting with a1:9 to 9:1 acetonitrile-water gradient to give2-(benzyloxy)-N-(5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)ethanesulfonamide.MS (ESI) m/z 422.1 (M+H)⁺.

(b)2-Hydroxy-N-(5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)ethanesulfonamide

A flask is charged with2-(benzyloxy)-N-(5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)ethanesulfonamide(90 mg, 0.214 mmol) and MeOH (5 mL), and the flask is flushed with N₂.10% Pd/C (22.7 mg, 0.021 mmol) is added to the mixture. The flask isflushed with H₂ and stirred under H₂ atmosphere at 50° C. overnight. Themixture is filtered and the filtrate is purified by silicachromatography eluting with a 0 to 4% methanol-DCM gradient to give2-hydroxy-N-(5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)ethanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.37 (t, J=6.2 Hz, 2H), 3.77 (s, 3H),3.80 (t, J=6.3 Hz, 2H), 4.96 (br. s., 1H), 6.70 (s, 1H), 7.10 (t, J=7.1Hz, 1H), 7.23 (td, J=7.6, 1.1 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.61 (d,J=7.8 Hz, 1H), 7.79 (t, J=2.3 Hz, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.55 (d,J=1.8 Hz, 1H), 10.12 (br. s., 1H). HRMS: (ESI) m/z 332.1072 [(M+H)⁺Calcdfor C₁₆H₁₈N₃O₃S 332.1063].

Example 2402-Methoxy-N-(5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)ethanesulfonamide

A flask is charged with 5-(1-methyl-1H-indol-2-yl)pyridin-3-amine(Example 100, 22 mg, 0.10 mmol), DCM (2 mL) and TEA (20 mg, 0.20 mmol).2-Chloroethanesulfonyl chloride (16 mg, 0.10 mmol) in DCM (0.5 mL) isadded dropwise at 0° C. The mixture is stirred over weekend at roomtemperature. The solvent is removed in vacuo and methanol (2 mL) and 5 Maqueous NaOH (3 mL) are added. The mixture is stirred at 60° C.overnight, concentrated in vacuo and the residue is extracted with DCM.The combined organic phase is dried over Na₂SO₄ and concentrated. Theresidue is purified on silica chromatography eluting with a 0 to 5%methanol-DCM gradient to give2-methoxy-N-(5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)ethanesulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.18 (s, 3H), 3.51 (t, J=5.7 Hz, 2H),3.70 (t, J=5.7 Hz, 2H), 3.77 (s, 3H), 6.70 (d, J=0.5 Hz, 1H), 7.10 (td,J=7.5, 1.0 Hz, 1H), 7.23 (ddd, J=8.2, 7.1, 1.1 Hz, 1H), 7.53 (d, J=8.3Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.78 (t, J=2.3 Hz, 1H), 8.46 (d, J=2.5Hz, 1H), 8.55 (d, J=2.0 Hz, 1H). HRMS: (ESI) m/z 346.1251 [(M+H)⁺ Calcdfor C₁₇H₂₀N₃O₃S: 346.1225].

Example 241 (a) 5-bromo-N,N-diethylpyridine-3-sulfonamide

To a suspension of 5-bromopyridine-3-sulfonamide (237 mg, 1 mmol) andK₂CO₃ (276 mg, 2 mmol) in DMF (1 mL) is added iodoethane (156 mg, 1mmol) in DMF (5 mL) via syringe pump over 2 hours. The mixture is thenstirred at room temperature overnight. Iodoethane (0.020 mL, 0.2 mmol)in DMF (1 mL) is added dropwise. The mixture is stirred over the weekendand filtered. The filtrate is purified by Xterra RP18 eluting with a 1:9to 9:1 acetonitrile-water gradient to give5-bromo-N,N-diethylpyridine-3-sulfonamide. MS (ESI) m/z 293.0, 295.1(M+H)⁺.

(b) N-ethyl-5-(1-methyl-1H-indol-2-yl)pyridine-3-sulfonamide

The method described in Example 241a also affordsN-ethyl-5-(1-methyl-1H-indol-2-yl)pyridine-3-sulfonamide as a product ofthe reaction. MS (ESI) m/z 265.0, 267.0 (M+H)⁺.

(c) N,N-diethyl-5-(1-methyl-1H-indol-2-yl)pyridine-3-sulfonamide

A flask is charged with 1-methyl-1H-indol-2-ylboronic acid (90 mg, 0.512mmol), 5-bromo-N,N-diethylpyridine-3-sulfonamide (100 mg, 0.341 mmol)and polymer supported Pd(PPh₃)₄ (189 mg, 0.017 mmol), and the flask isflushed with N₂ for 5 min. 1,4-Dioxane (10 mL) and 2M K₂CO₃ in water(0.512 mL, 1.023 mmol) are added under N₂ and the mixture is stirred at90° C. under N₂ for 2 h. The mixture is then cooled to room temperatureand DMF (4 mL) is added. The mixture is concentrated in vacuo and theresidue is filtered and the filtrate is purified by Xterra RP18 elutingwith a 1:9 to 9:1 acetonitrile-water gradient to giveN,N-diethyl-5-(1-methyl-1H-indol-2-yl)pyridine-3-sulfonamide. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.10 (t, J=7.1 Hz, 6H), 3.29 (d, J=7.1 Hz, 4H),3.80 (s, 3H), 6.85 (s, 1H), 7.08-7.14 (m, 1H), 7.26 (td, J=7.71, 1.26Hz, 1H), 7.56 (dd, J=8.3, 0.5 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.33 (t,J=2.1 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H), 9.10 (d, J=2.2 Hz, 1H). HRMS:(ESI) m/z 344.1428 [(M+H)⁺ Calcd for C₁₈H₂₂N₃O₂S 344.1427].

Example 242 N-ethyl-5-(1-methyl-1H-indol-2-yl)pyridine-3-sulfonamide

N-Ethyl-5-(1-methyl-1H-indol-2-yl)pyridine-3-sulfonamide is processedaccording to the method described in Example 241c to giveN-ethyl-5-(1-methyl-1H-indol-2-yl)pyridine-3-sulfonamide. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.02 (t, J=7.2 Hz, 3H), 2.92 (q, J=7.2 Hz, 2H), 3.81(s, 3H), 6.83 (s, 1H), 7.12 (t, J=7.1 Hz, 1H), 7.26 (td, J=7.6, 1.1 Hz,1H), 7.56 (d, J=8.3 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.31 (t, J=2.2 Hz,1H), 8.97 (d, J=2.3 Hz, 1H), 9.08 (d, J=2.2 Hz, 1H). HRMS: (ESI) m/z316.1126 [(M+H)⁺Calcd for C₁₆H₁₈N₃O₂S 316.1114].

Example 243 In-Vitro Assay for Aldosterone Synthase Inhibition

The activities of a compound according to the present invention can beassessed by the following in vitro method well-described in the art. SeeFiebeler, A et al. (2005), “Aldosterone Synthase Inhibitor AmelioratesAngiotensin II-Induced Organ Damage,” Circulation, 111:3087-3094.

In particular, the inhibition of aldosterone and cortisol secretion invitro can be determined by the following assay.

The cell line NCI-H295R was originally isolated from an adrenocorticalcarcinoma and has been characterized in the literature through thestimulable secretion of steroid hormones and the presence of the enzymesessential for steroidogenesis. The cells show the physiological propertyof zonally undifferentiated human foetal adrenocortical cells which,however, have the capacity to produce the steroid hormones which areformed in the three phenotypically distinguishable zones in the adultadrenal cortex. Thus, the NCI-H295R cells have CYP11B2 (aldosteronesynthase) and CYP11B1 (steroid 11-hydroxylase).

The human adrenocortical carcinoma NCI-H295R cell line is obtained fromAmerican Type Culture Collection (Manassas, Va.).Insulin/transferrin/selenium (ITS)-A supplement (100×), DMEM/F-12,antibiotic/antimycotic (100×), and fetal calf serum (FCS) are purchasedfrom Invitrogen (Carlsbad, Calif.). Anti-mouse PVT scintillationproximity assay (SPA) beads and NBS 96-well plates are obtained fromAmersham (Piscataway, N.J.) and Corning (Acton, Mass.), respectively.Clear bottom 96-well flat bottom plates are purchased from Costar(Corning, N.Y.). Aldosterone and angiotensin (Ang II) are purchased fromSigma (St. Louis, Mo.). D[1,2,6,7-3H(N)]aldosterone and[1,2,6,7-3H(N)]cortisol are acquired from PerkinElmer (Boston, Mass.).Nu-serum is a product of BD Biosciences (Franklin Lakes, N.J.).

For in vitro measurement of aldosterone and cortisol activity, humanadrenocortical carcinoma NCI-H295R cells are seeded in NBS 96-wellplates at a density of 25,000 cells/well in 100 μL of a growth mediumcontaining DMEM/F12 supplemented with 10% FCS, 2.5% Nu-serum, 1 μgITS/ml, and 1× antibiotic/antimycotic. The medium is changed afterculturing for 3 days at 37° C. under an atmosphere of 5% CO₂/95% air. Onthe following day, cells are rinsed with 100 μL of DMEM/F12 andincubated in quadruplicate wells at 37° C. for 24 hours with 100 μL oftreatment medium containing a cell stimulant and a compound at differentconcentrations. The test substance is added in a concentration rangefrom 0.2 nanomolar to 16 micromolar. Cell stimulants which can be usedare angiotensin-II (1 micormolar), potassium ions (16 millimolar),forskolin (10 micromolar) or a combination of two stimulants. At the endof incubation, the excretion of aldosterone and cortisol into theculture medium can be detected and quantified by commercially available,specific monoclonal antibodies in radioimmunoassays in accordance withthe manufacturer's instructions.

Measurement of aldosterone can also be performed using a 96-well plateformat. Each test sample is incubated with 0.02 μCi ofD[1,2,6,7-3H(N)]aldosterone and 0.3 μg of anti-aldosterone antibody inphosphate-buffered saline (PBS) containing 0.1% Triton X-100, 0.1%bovine serum albumin, and 12% glycerol in a total volume of 200 μL atroom temperature for 1 hour. Anti-mouse PVT SPA beads (50 μL) are thenadded to each well and incubated overnight at room temperature prior tocounting in a Microbeta plate counter. The amount of aldosterone in eachsample is calculated by comparing with a standard curve generated usingknown quantities of the hormone. Measurement of cortisol can beperformed in a manner similar to that of aldosterone, except that[1,2,6,7-3H(N)]cortisol is used.

Inhibition of the release of a steroid can be used as a measure of therespective enzyme inhibition by the added test compounds. Thedose-dependent inhibition of enzymatic activity by a compound iscalculated by means of an inhibition plot which is characterized by anIC₅₀. The IC₅₀ values for active test compounds are ascertained by asimple linear regression analysis in order to construct inhibition plotswithout data weighting. The inhibition plot is calculated by fitting a4-parameter logistic function to the raw data points using the leastsquares method. The equation of the 4-parameter logistic function iscalculated as follows: Y=(d−a)/((1+(x/c)(b)+a) where: a=minimum,b=slope, c=IC₅₀, d=maximum, x=inhibitor concentrations.

TABLE 1 Inhibitory Activity of Compounds Aldosterone Cortisol cellsecretion cell secretion Example IC₅₀ (nM) IC₅₀ (nM)  6 1 7  15 27 447 33 14 662  42 30 600  65 10 240  90 40 400 101 2 37 106 85 530 107 9220 123 78 650 138 43 326 171 3 168 180 2 3 186 21 390 192 4 20 196 3 19206 2 213 209 23 788 214 56 377 216 (one enantiomer) 32 600 216 (otherenantiomer) 35 1230 217 4 22 226 36 345 228 105 >1000 229 5 125 231 2 51236 21 1100 237 5 1611 238 44 >1000 242 23 >1000

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents are considered tobe within the scope of the present invention and are covered by thefollowing claims. The appropriate components, processes, and methods ofthose patents, applications and other documents may be selected for thepresent invention and embodiments thereof.

1. A compound of Formula I:

wherein: R^(1a), R^(2a), R^(3a), and R^(4a) are each independentlyhydrogen, halogen, cyano, hydroxy, alkoxy, alkyl, alkenyl, oralkoxycarbonyl; R^(5a) is hydrogen, halogen, cyano, alkyl, alkenyl,arylalkyl, heteroarylalkyl, aminocarbonyl, alkylaminocarbonyl,carboxylate, alkoxycarbonyl, heterocyclylcarbonyl, aryl, or heteroaryl;R^(6a) and R^(7a) are each independently hydrogen, halogen, hydroxy,alkoxy, amino, alkyl, sulfonyl, —O-sulfonyl, alkylamino, heterocyclyl,aminocarbonyl, carboxylate, or alkoxycarbonyl; R^(8a) is hydrogen,alkyl, arylalkyl, heteroarylalkyl, alkoxycarbonyl, sulfonyl, aroyl,aryl, or heteroaryl; and pharmaceutically acceptable salts, polymorphs,rotamers, prodrugs, enantiomers, hydrates, and solvates thereof; withthe proviso that at least one of R^(1a)-R^(8a) is other than hydrogen;and when R^(3a) is lower alkyl or halogen, then at least one of R^(1a),R^(2a) and R^(4a)-R^(8a) is other than hydrogen; and when R^(5a) iscyano or lower alkyl optionally substituted with cyano,—C(O)-piperidine, amino, alkylamino, dialkylamino, carboxylate,alkoxycarbonyl, aminocarbonyl, or heterocyclyl, then at least one ofR^(1a)-R^(4a) and R^(6a)-R^(8a) is other than hydrogen; and when R^(7a)is imidazolyl, then at least one of R^(1a)-R^(6a) and R^(8a) is otherthan hydrogen; and when R^(8a) is lower alkyl, arylalkyl oralkoxycarbonyl, then at least one of R^(1a)-R^(7a) is other thanhydrogen; and when R^(5a) is lower alkyl and R^(8a) is alkyl substitutedwith carboxylate or PO₃R²¹R²² wherein R²¹ and R²² are each independentlyhydrogen or lower alkyl, then at least one of R^(1a)-R^(4a) and R^(6a)and R^(7a) is other than hydrogen; and when R^(3a) is halogen and R^(5a)and R^(8a) are independently lower alkyl optionally substituted withcarboxylate, alkoxycarbonyl, or —C(O)-piperidine, then at least one ofR^(1a), R^(2a), R^(4a), R^(6a) and R^(7a) is other than hydrogen; andwhen R^(5a) is lower alkenyl substituted with heteroaryl and R^(8a) islower alkyl, then at least one of R^(1a)-R^(4a), R^(6a) and R^(7a) isother than hydrogen; and when R^(3a) is halogen or lower alkyl andR^(5a) is lower alkyl substituted with dialkylamino,dialkylaminocarbonyl, carboxylate, alkoxycarbonyl or aminocarbonyl, thenat least one of R^(1a), R^(2a), R^(4a), and R^(6a)-R^(8a) is other thanhydrogen; and when R^(3a) is —O-benzyl and R^(5a) is alkyl-NH₂, then atleast one of R^(1a), R^(2a), R^(4a), and R^(6a)-R^(8a) is other thanhydrogen; and when R^(2a) and R^(3a) are each alkoxy and R^(5a) iscyano, then at least one of R^(1a), R^(4a), and R^(6a)-R^(8a) is otherthan hydrogen; and when R^(1a) and R^(3a) are each halogen and R^(5a) isalkyl-NH₂, then at least one of R^(2a), R^(4a), and R^(6a)-R^(8a) isother than hydrogen; and when R^(2a) is alkoxycarbonyl and R^(4a) ishalogen, then at least one of R^(1a), R^(3a), R^(5a) and R^(6a)-R^(8a)is other than hydrogen; and when R^(5a) is alkyl and R^(7a) is—OCH₂—(N-methylpyrrolidine), then at least one of R^(1a)-R^(4a), R^(6a)and R^(8a) is other than hydrogen; and when R^(3a) is cycloalkyl andR^(5a) is alkyl-NH₂, then at least one of R^(1a), R^(2a), R^(4a), andR^(6a)-R^(8a) is other than hydrogen; and when R^(3a) is alkylsubstituted with aroyl, and R⁵ and R⁸ are each independently hydrogen orlower alkyl, then at least one of R^(1a), R^(2a), and R^(4a) is otherthan hydrogen.
 2. A compound of Formula II:

wherein: R^(2q) is hydrogen or halogen; R^(3q) is hydrogen, halogen, orcyano; R^(8q) is hydrogen, alkyl, or cyano; R^(7q) is hydrogen, halogen,alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl, —NR′—SO₂-alkyl,—NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl, —NR′—C(O)—O-alkyl, haloalkyl, oralkyl optionally substituted with heterocyclyl, —NR′—SO₂-alkyl,—NR′—SO₂-haloalkyl, NR′—C(O)-alkyl, NR′—C(O)-heterocycyl,—NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl; R^(8q) is hydrogen, alkyl,hydroxyalkyl, -alkyl-OC(O)-alkyl, carboxylate, alkoxycarbonyl, orarylalkyl substituted with alkyl, or aroyl substituted with cyano and/oralkyl, or -alkyl-O-aryl substituted with alkoxycarbonyl; each R′ isindependently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl; andpharmaceutically acceptable salts, polymorphs, rotamers, prodrugs,enantiomers, hydrates, and solvates thereof; with the proviso that atleast one of R^(2q), R^(3q), R^(5q), R^(7q) and R^(8q) is other thanhydrogen; and when R^(8q) is lower alkyl or alkoxycarbonyl, then atleast one of R^(2q), R^(3q), R^(5q) and R^(7q) is other than hydrogen;and when R^(5q) is cyano, then at least one of R^(2q), R^(3q), andR^(8q) is other than hydrogen.
 3. The compound according to claim 2,wherein R^(7q) is alkoxy or alkyl substituted with heterocyclyl andR^(8q) is alkyl.
 4. The compound according to claim 2, wherein R^(2q) ishydrogen or halogen; R^(3q) is hydrogen, or halogen; R^(5q) is hydrogenor cyano; R^(7q) is alkyl optionally substituted with heterocyclyl,—NR′—SO₂-alkyl, —NR′—SO₂-haloalkyl, NR′—C(O)-alkyl,NR′—C(O)-heterocyclyl, —NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl; R′ isindependently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl; and R^(8q) ishydrogen, or C₁₋₆alkyl.
 5. The compound according to claim 2, whereinR^(2q) is hydrogen or halogen; R^(3q) is hydrogen, or halogen; R^(5q) ishydrogen or cyano; R^(7q) is C₁₋₄alkyl optionally substituted withheterocyclyl, —NR′—SO₂-haloC₁₋₄alkyl, NR′—C(O)—NR′—C(O)-heterocyclyl,—NR′—C(O)—NR′—C₁₋₄alkyl, or —NR′—C(O)—O—C₁₋₄alkyl; R′ is independentlyhydrogen, or C₁-C_(a)-alkyl; and R^(8q) is hydrogen, or C₁₋₆alkyl. 6.The compound according to claim 2, wherein R^(7q) is C₁₋₄alkylsubstituted with —NR′—SO₂—C₁₋₄alkyl, —NR′—SO₂-haloC₁₄alkyl, orNR′—C(O)—C₁₋₄alkyl; R′ is independently hydrogen, or C₁-C₄-alkyl; andR^(8q) is hydrogen, methyl, or ethyl.
 7. A compound of Formula III:

wherein: R^(2b) is hydrogen or halogen; R^(3b) is hydrogen, halogen, orcyano; R^(5b) is alkyl; R^(7b) is hydrogen, halogen, alkoxy,—OSO₂-heterocyclyl, —O-arylalkyl, —NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl,—NR′—C(O)—O-alkyl, haloalkyl, or alkyl optionally substituted withheterocyclyl, NR′—C(O)-alkyl, —NR′—C(O)—NR′-alkyl,NR′—C(O)-heterocyclyl, or —NR′—C(O)—O-alkyl; R^(8b) is hydrogen, alkyl,hydroxyalkyl, -alkyl-OC(O)-alkyl, carboxylate, alkoxycarbonyl, orarylalkyl substituted with alkyl, or aroyl substituted with cyano and/oralkyl, or -alkyl-O-aryl substituted with alkoxycarbonyl; each R′ isindependently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl; andpharmaceutically acceptable salts, polymorphs, rotamers, prodrugs,enantiomers, hydrates, and solvates thereof.
 8. The compound accordingto claim 7, wherein R^(2b) is hydrogen or halogen; R^(3b) is hydrogen,halogen, or cyano; R^(5b) is C₁₋₄alkyl; R^(7b) is hydrogen, halogen,C₁₋₄alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl, —NR′—SO₂—C₁₋₄alkyl,—NR′—C(O)—C₁₋₄alkyl, —NR′—C(O)—NR′—C₁₋₄alkyl, haloalkyl, or C₁₋₄alkyloptionally substituted with heterocyclyl, —NR′—SO₂-halo C₁₋₄alkyl,NR′—C(O)—C₁₋₄alkyl, NR′—C(O)-heterocyclyl, or —NR′—C(O)—O—C₁₋₄alkyl;R^(8b) is hydrogen, C₁₋₄alkyl, hydroxyalkyl, —C₁₋₄alkyl-OC(O)—C₁₋₄alkyl,carboxylate, alkoxycarbonyl, or arylalkyl substituted with C₁₋₄alkyl, oraroyl substituted with cyano and/or C₁₋₄alkyl, or —C₁₋₄alkyl-O-arylsubstituted with alkoxycarbonyl; each R′ is independently hydrogen,C₁-C₄-alkyl, or C₃-C₆-cycloalkyl; and pharmaceutically acceptable salts,polymorphs, rotamers, prodrugs, enantiomers, hydrates, and solvatesthereof.
 9. The compound according to claim 7, wherein R^(2b) ishydrogen or halogen; R^(3b) is hydrogen, halogen, or cyano; R^(5b) ismethyl, ethyl or isopropyl; R^(7b) is C₁₋₄alkyl substituted with—NR′—SO₂—C₁₋₄alkyl, —NR′—SO₂-haloC₁₋₄alkyl, NR′—C(O)—C₁₋₄alkyl, or—NR′—C(O)—NR′—C₁₋₄alkyl; R^(8b) is hydrogen, methyl or ethyl; each R′ isindependently hydrogen, or C₁-C₄-alkyl.
 10. A compound of Formula IV:

wherein: R^(2c) is hydrogen or halogen; R^(3c) is hydrogen, halogen, orcyano; R^(5c) is cyano; and R^(7c) is hydrogen, halogen alkoxy,—OSO₂-heterocyclyl, —O-arylalkyl, —NR′—SO₂-alkyl, —NR′—C(O)-alkyl,—NR′—C(O)—NR′-alkyl, —NR′—C(O)—O-alkyl or alkyl optionally substitutedwith heterocyclyl, —NR′—SO₂-alkyl, —NR′—SO₂-haloalkyl, NR′—C(O)-alkyl,NR′—C(O)-heterocyclyl, —NR′—C(O)—NR′-alkyl, or —NR′—C(O)—O-alkyl; R^(8c)is alkyl; each R′ is independently hydrogen, C₁-C₄-alkyl, orC₃-C₆-cycloalkyl; and pharmaceutically acceptable salts, polymorphs,rotamers, prodrugs, enantiomers, hydrates, and solvates thereof.
 11. Thecompound according to claim 10, wherein R^(2c) is hydrogen or halogen;R^(3c) is hydrogen, halogen, or cyano; R^(5c) is cyano; and R^(7c) ishydrogen, halogen, C₁₋₄alkoxy, —OSO₂-heterocyclyl, —O-arylalkyl,—NR′—SO₂—C₁₋₄ alkyl, —NR′—C(O)—C₁₋₄ alkyl, —NR′—C(O)—NR′—C₁₋₄ alkyl,—NR′—C(O)—O—C₁ alkyl or C₁₋₄ alkyl optionally substituted withheterocyclyl, —NR′—SO₂—C₁₋₄ alkyl, —NR′—SO₂-halo C₁₋₄ alkyl,NR′—C(O)—C₁₋₄ alkyl, NR′—C(O)-heterocyclyl, —NR′—C(O)—NR′—C₁₋₄ alkyl, or—NR′—C(O)—O—C₁₋₄ alkyl; R^(8c) is C₁₋₄ alkyl; and each R′ isindependently hydrogen, C₁-C₄-alkyl, or C₃-C₆-cycloalkyl.
 12. Thecompound according to claim 10, wherein R^(2c) is hydrogen or halogen;R^(3c) is hydrogen, or halogen; R^(5c) is cyano; and R^(7c) is C₁₋₄alkyl optionally substituted with —NR′—SO₂—C₁₋₄ alkyl, —NR′—SO₂-haloC₁₋₄ alkyl, NR′—C(O)—C₁₋₄ alkyl; R^(8c) is C₁₋₄ alkyl; each R′ isindependently hydrogen, methyl, ethyl or propyl.
 13. The compoundaccording to claim 10, wherein R^(7c) is C₁₋₄ alkyl substituted with—NR′—SO₂—C₁₋₄ alkyl, —NR′—SO₂-halo C₁₋₄ alkyl, NR′—C(O)—C₁₋₄ alkyl; andeach R′ is independently hydrogen or C₁-C₄-alkyl.
 14. (canceled)
 15. Amethod of treating an aldosterone synthase associated state in asubject, comprising: administering to said subject a therapeuticallyeffective amount of the compound of Formulae I according to claim 1 suchthat said aldosterone synthase associated state in said subject istreated. 16-17. (canceled)
 18. The method of claim 15, wherein saidaldosterone synthase associated state is a cardiovascular diseaseselected from heart failure, congestive heart failure, arrhythmia,diastolic dysfunction, left ventricular diastolic dysfunction, diastolicheart failure, impaired diastolic filling, systolic dysfunction,ischemia, hypertropic cardiomyopathy, sudden cardiac death, myocardialand vascular fibrosis, impaired arterial compliance, myocardial necroticlesions, vascular damage, myocardial infarction, left ventricularhypertrophy, decreased ejection fraction, cardiac lesions, vascular wallhypertrophy, endothelial thickening, or fibrinoid necrosis of coronaryarteries.
 19. (canceled)
 20. A method for treating a subject for heartfailure, congestive heart failure, arrhythmia, diastolic dysfunction,left ventricular diastolic dysfunction, diastolic heart failure,impaired diastolic filling, systolic dysfunction, ischemia, hypertropiccardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis,impaired arterial compliance, myocardial necrotic lesions, vasculardamage, myocardial infarction, left ventricular hypertrophy, decreasedejection fraction, cardiac lesions, vascular wall hypertrophy,endothelial thickening, fibrinoid necrosis of coronary arteries, renaldysfunction, liver diseases, cerebrovascular diseases, vasculardiseases, retinopathy, neuropathy, insulinopathy, edema, endothelialdysfunction, baroreceptor dysfunction, migraine headaches, orhypertension, comprising: administering to said subject an effectiveamount of the compound of Formula I according to claim 1 such that saidsubject is treated.
 21. The method of claim 20, wherein said subject ishuman. 22-23. (canceled)
 24. A pharmaceutical composition, comprising aneffective amount of the compound according to claim 1, and apharmaceutically acceptable carrier or diluent.
 25. The pharmaceuticalcomposition of claim 24, further comprising a second agent.
 26. Thepharmaceutical composition of claim 25, wherein said second agent is anHMG-Co-A reductase inhibitor, an angiotensin II receptor antagonist,angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker(CCB), a dual angiotensin converting enzyme/neutral endopeptidase(ACE/NEP) inhibitor, an endothelin antagonist, a renin inhibitor, adiuretic, an ApoA-I mimic, an anti-diabetic agent an obesity-reducingagent, an aldosterone receptor blocker, an endothelin receptor blocker,or a CETP inhibitor 27-30. (canceled)